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1
Benarab, Ammar. „Harnessing endothelial lipid signaling for ischemic stroke protection“. Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5197.
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Justification : La fonction cérébrovasculaire est essentielle à la santé du cerveau, et les voies de protection vasculaire endogènes peuvent fournir des cibles thérapeutiques pour les troubles neurologiques. La signalisation S1P (sphingosine 1-phosphate) coordonne les fonctions vasculaires dans d'autres organes et les modulateurs S1P1 (récepteur S1P-1), y compris le fingolimod, sont prometteurs pour le traitement de l'AVC ischémique et hémorragique. Cependant, S1P1 coordonne également le trafic lymphocytaire, et les lymphocytes sont actuellement considérés comme la principale cible thérapeutique pour la modulation de S1P1 dans les accidents vasculaires cérébraux. Objectif : Aborder les rôles et les mécanismes d'engagement de la cellule endothéliale S1P1 dans le cerveau naïf et ischémique et son potentiel en tant que cible pour la thérapie cérébrovasculaire. Méthodes et résultats : En utilisant la modulation spatiale de la fourniture et de la signalisation S1P, nous démontrons un rôle protecteur vasculaire critique pour S1P1 endothélial dans le cerveau de souris. Avec un journaliste de signalisation S1P1, nous révélons que la polarisation abluminale protège S1P1 des ligands endogènes et synthétiques circulants après maturation de la barrière hémato-neurale, limitant la signalisation homéostatique à un sous-ensemble de cellules endothéliales artériolaires. La signalisation S1P1 maintient les fonctions endothéliales caractéristiques dans le cerveau naïf et se développe pendant l'ischémie par l'engagement de la fourniture S1P autonome des cellules. La perturbation de cette voie par une déficience sélective des cellules endothéliales dans la production, l'exportation ou le récepteur S1P1 de S1P exacerbe considérablement les lésions cérébrales dans les modèles permanents et transitoires d'AVC ischémique. En revanche, la lymphopénie profonde induite par la perte du lymphocyte S1P1 n'offre une protection modeste que dans le cadre d'une reperfusion. Dans le cerveau ischémique, la cellule endothéliale S1P1 soutient la fonction de barrière hémato-encéphalique, la perméabilité microvasculaire et le réacheminement du sang vers le tissu cérébral hypoperfusé par le biais d'anastomoses collatérales. Le renforcement de ces fonctions par un engagement pharmacologique supplémentaire du pool de récepteurs endothéliaux avec une barrière hémato-encéphalique pénétrant un agoniste sélectif de S1P1 peut réduire davantage l'expansion de l'infarctus cortical dans un délai thérapeutiquement pertinent et indépendamment de la reperfusion. Conclusions : Cette étude fournit des preuves génétiques pour soutenir un rôle central de l'endothélium dans le maintien de la perfusion et de la perméabilité microvasculaire dans la pénombre ischémique qui est coordonnée par la signalisation S1P et peut être exploitée pour la neuroprotection avec des agonistes S1P1 pénétrant la barrière hémato-encéphaliqueRationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs and S1P1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P1 modulation in stroke. Objective: To address roles and mechanisms of engagement of endothelial cell S1P1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy. Methods and results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P1 in the mouse brain. With an S1P1 signaling reporter, we reveal that abluminal polarization shields S1P1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by an endothelial cell-selective deficiency in S1P production, export, or the S1P1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P1-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P1 agonists
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Cheong, Fei Ying. „Regulation of lipid signaling at the Golgi by the lipid phosphatases hSAC1 and OCRL1“. [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:16-opus-71011.
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Herman, Moreno Maria Dolores. „Structural studies of proteins in apoptosis and lipid signaling“. Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8212.
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Signaling pathways control the fate of the cell. For example, they promote cell survival or commit the cell to death (apoptosis) in response to cell injury or developmental stimuli, decisions, which are vital for the proper development and functioning of metazoan. Tight control of such pathways is essential; dysregulation of apoptosis can disrupt the delicate balance between cell proliferation and cell death ending up in pathological processes, including cancer, autoimmunity diseases, inflammatory diseases, or degenerative disorders. We have used a structural genomic approach to study the structure and function of key proteins involved in apoptosis and lipid signaling: the antiapoptotic Bcl-2 family member Bfl-1 in complex with a Bim peptide, the BIR domains of the Inhibitor of Apoptosis (IAP) family members, cIAP2 and NAIP and the a lipid kinase YegS. The structural analysis of the apoptosis regulatory proteins has revealed important information on the structural determinants for recognition of interacting proteins, which can now assist in the development of therapeutic drugs for human diseases. The structural and complementing biochemical studies of the lipid kinase YegS have reveled the first detailed information on a lipid kinase and explained important aspects of its structure-function relationship. Finally, one subject of this work aim to solve what is arguably the most challenging problem in structural projects – to obtain a high production level of proteins suitable for structural studies. We have developed a highthroughput protein solubility screening, the colony filtration (CoFi) blot, which allows soluble clones to be identified from large libraries of protein variants and now constitute a powerful tool for solving difficult protein production problems.
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Aivazian, Dikran A. (Dikran Arvid) 1971. „Lipid-protein interactions of immunoreceptor signaling subunit cytoplasmic domains“. Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8583.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2001.Vita.
Includes bibliographical references (leaves 116-131).
Protein-lipid interactions are emerging as key components of cellular processes such as protein and membrane trafficking and cell-cell signaling. Many proteins bind lipid reversibly, including cytoplasmic proteins involved in signal transduction, such as Ras and Src. Membrane binding is vital for the function of these signaling proteins both through co-localization with other signaling proteins as well as effects of lipid on intrinsic activities. In this thesis, protein-lipid interactions of subunits of key antigen recognition receptors of the immune system are investigated. The proteins studied are the cytoplasmic domains of immunoreceptor signaling subunits that mediate transmembrane signal transduction in response to receptor engagement. The cytoplasmic domains derive from the T cell receptor, the B cell receptor, Fe receptors and Natural Killer cell stimulatory receptors. The TCR, CD3, CD3, CD3, ... and DAP12 cytoplasmic domains all bind lipid, whereas those of B cell receptor Iga and Igp do not. While all of these proteins are unstructured in solution, ... and CD3 undergo extensive increases in secondary structure upon lipid binding. Lipid binding of ... is found to inhibit its accessibility to kinase-mediated phosphorylation. Based on these results it is proposed that interactions with lipid may regulate the function of receptor cytoplasmic domains, as with many cytosolic proteins involved in signaling processes.
by Dikran A. Aivazian.
Ph.D.
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Secor, Jordan Douglas. „Phytochemical Antioxidants Induce Membrane Lipid Signaling in Vascular Endothelial Cells“. The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338391553.
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Cody, West Kime. „Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program“. Kyoto University, 2018. http://hdl.handle.net/2433/232302.
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Kline, Michelle A. „Membrane cholesterol regulates vascular endothelial cell viability, function, and lipid signaling“. Connect to resource, 2008. http://hdl.handle.net/1811/32175.
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Sadhukhan, Sushabhan. „Metabolism & Signaling of 4-Hydroxyacids: Novel Metabolic Pathways and Insight into the Signaling of Lipid Peroxidation Products“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1339171892.
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Kilaru, Aruna. „Discovery of Anandamide, a Novel Lipid Signaling Molecule in Moss and Its Implications“. Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/4771.
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Herrera-Velit, Patricia. „Bacterial lipopolysaccharides signaling pathways in mononuclear phagocytes involve protein and lipid kinases“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0034/NQ27161.pdf.
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11
Xia, Ye. „THE ROLE OF CUTICLE, FATTY ACIDS, AND LIPID SIGNALING IN PLANT DEFENSE“. UKnowledge, 2010. http://uknowledge.uky.edu/plantpath_etds/10.
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Systemic acquired resistance (SAR) is initiated upon recognition of specific microbial effectors by cognate plant resistance proteins and immunizes distal tissues of plants against secondary infections. SAR involves the generation of a mobile signal at the site of primary infection, which then translocates to and activates defense responses in the distal tissues via some unknown mechanism(s). This study shows that an ACYL CARRIER PROTEIN 4 (ACP4), GLABRA1 (GL1) and ACYL CARRIER BINDING PROTEINS (ACBP) are required for the processing of the mobile SAR signal in distal tissues of Arabidopsis. Although acp4, gl1 and acbp plants generate the mobile signal, they are unable to respond to this signal to induce systemic immunity. A defective SAR in acp4, gl1 and acbp plants is not associated with salicylic acid (SA)-, methyl SA-, or jasmonic acid-mediated pathways but is related to the presence of an abnormal cuticle on acp4, gl1 and acbp plants. Other genetic mutations impairing the cuticle also compromised SAR. An intact cuticle was only necessary during the time when the mobile signal is generated and translocated to the distal tissues. A novel role for the plant cuticle as the site for SAR-related molecular signaling is demonstrated.
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Yecies, Jessica. „SREBP: A Key Effector of mTORC1 Signaling in Metabolism and Cancer“. Thesis, Harvard University, 2011. http://dissertations.umi.com/gsas.harvard:10023.
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The mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth and proliferation, is aberrantly activated in cancer, genetic tumor syndromes and obesity. Much progress has been made to understand the upstream pathways that regulate mTORC1, most of which converge upon its negative regulator, the Tuberous Sclerosis Complex (TSC) 1-TSC2 complex. However, the cell intrinsic consequences of aberrant mTORC1 activation remain poorly characterized. Using systems in which mTORC1 is constitutively activated by genetic loss of TSC1 or TSC2 and pharmacologically inhibited by treatment with an mTORC1-specific inhibitor rapamycin, we have identified that mTORC1 controls specific aspects of cellular metabolism, including glycolysis, the pentose phosphate pathway, and de novo lipogenesis. Induction of the pentose phosphate pathway and de novo lipogenesis is achieved by activation of a transcriptional program affecting metabolic gene targets of sterol regulatory element-binding protein (SREBP). We have demonstrated that mTORC1 stimulates the accumulation of processed, active SREBP, although details of the molecular mechanism remain to be elucidated. To understand the physiological and pathological relevance of mTORC1-dependent activation of SREBPs and lipogenesis, we explored these findings in the liver and in cancer. While we find that the induction of hepatic SREBP1c and lipogenesis by insulin requires mTORC1, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We demonstrate that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. In cancer, our initial findings demonstrate that mTORC1 plays a role downstream of TSC-deficiency and oncogenic PIK3CA and K-Ras to activate lipogenic SREBP targets and de novo lipogenesis. Further studies of the connection between mTORC1 and SREBPs in disease may offer insights into novel therapeutic approaches.
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Unnerståle, Sofia. „NMR Investigations of Peptide-Membrane Interactions, Modulation of Peptide-Lipid Interaction as a Switch in Signaling across the Lipid Bilayer“. Licentiate thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-59534.
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The complexity of multi cellular organisms demands systems that facilitate communicationbetween cells. The neurons in our brains for instance are specialized in this cell-cellcommunication. The flow of ions, through their different ion channels, across the membrane, isresponsible for almost all of the communication between neurons in the brain by changing theneurons membrane potentials. Voltage-gated ion channels open when a certain thresholdpotential is reached. This change in membrane potential is detected by voltage-sensors in the ionchannels. In this licentiate thesis the Homo sapiens voltage- and calcium-gated BK potassiumchannel (HsapBK) has been studied. The NMR solution structure of the voltage-sensor ofHsapBK was solved to shed light upon the voltage-gating in these channels. Structures of othervoltage-gated potassium channels (Kv) have been determined by other groups, enablingcomparison among different types of Kv channels. Interestingly, the peptide-lipid interactions ofthe voltage-sensor in HsapBK are crucial for its mechanism of action.Uni cellular organisms need to sense their environment too, to be able to move towardsmore favorable areas and from less favorable ones, and to adapt their gene profiles to currentcircumstances. This is accomplished by the two-component system, comprising a sensor proteinand a response regulator. The sensor protein transfers signals across the membrane to thecytoplasm. Many sensor proteins contain a HAMP domain close to the membrane that isinvolved in transmitting the signal. The mechanism of this transfer is not yet revealed. Ourstudies show that HAMP domains can be divided into two groups based on the membraneinteraction of their AS1 segments. Further, these two groups are suggested to work by differentmechanisms; one membrane-dependent and one membrane-independent mechanism.Both the voltage-gating mechanism and the signal transduction carried out by HAMPdomains in the membrane-dependent group, demand peptide-lipid interactions that can be readilymodulated. This modulation enables movement of peptides within membranes or within thelipid-water interface. These conditions make these peptides especially suitable for NMR studies.
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Mok, Crystal Yin Lam. „The role of lipid accumulation and insulin signaling in adipose tissue macrophage polarization“. Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648349.
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Rapovy, Shannon Marie. „Characterization of the Physico-chemical Properties of the Novel Signaling Lipid Diacylglycerol Pyrophosphate“. Kent State University Honors College / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1335810423.
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Cheong, Fei Ying [Verfasser], und Peter PD [Akademischer Betreuer] Mayinger. „Regulation of lipid signaling at the Golgi by the lipid phosphatases hSAC1 and OCRL1 / Fei Ying Cheong ; Betreuer: Peter PD Mayinger“. Heidelberg : Universitätsbibliothek Heidelberg, 2007. http://d-nb.info/1178796647/34.
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Gyllberg, Hanna. „Prion-infection and Cellular Signaling : Influence of scrapie-infection on lipid raft-associated proteins“. Doctoral thesis, Stockholm : Department of Biochemistry and Biophysics, Stockholm university, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7115.
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Rimmerman, Neta. „The signaling properties in sensory neurons of the novel endogenous lipid N-palmitoyl glycine“. [Bloomington, Ind.] : Indiana University, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3283743.
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Thesis (Ph.D.)--Indiana University, Dept. of Psychological and Brain Sciences and Program in Neuroscience, 2007.Source: Dissertation Abstracts International, Volume: 68-10, Section: B, page: 6514. Adviser: J. Michael Walker. Title from dissertation home page (viewed May 21, 2008).
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Chapagai, Danda P. „Biochemical Characterization of SBIP-470 and its role in SA-mediated Signaling in Plants“. Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etd/2428.
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Salicylic acid binding protein 2 (SABP2) is known to play a key role in Salicylic acid mediated defense pathway. SBIP-470 is SABP2 interacting protein that might be putatively involved in transfer of lipids. SBIP-470 was cloned without the signal peptide and expressed in E. coli. In vitro lipid binding assay using recombinant SBIP-470 failed to detect lipid binding. In vitro lipid transfer assay showed recombinant SBIP-470 does not transfer phospholipid. Study has shown that SBIP-470 is highly inducible upon infection with viral as well as bacterial pathogens. Induction of SBIP-470 expression upon the TMV infection most likely depends upon the SABP2 while its expression upon non-host bacterial pathogens is most probably inhibited by the SABP2. A study of Arabidopsis knockout mutants (ltp12 mutant and ltp2 mutant) lacking the SBIP-470 homolog genes showed defects in growth phenotype, and they were found susceptible to bacterial pathogens.
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BERTOLIO, REBECCA. „Sterol Regulatory Element Binding Protein couples mechanical cues to lipid metabolism“. Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2963753.
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Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid biosynthesis and adipogenesis by controlling the expression of several enzymes required for endogenous cholesterol, fatty acid, triacylglycerol, and phospholipid synthesis1. In vertebrates, SREBP activation is mainly controlled by a complex and well-characterized feedback mechanism mediated by cholesterol, a crucial bio-product of the SREBP-activated mevalonate pathway.
In this work, we identified the acto-myosin contractility and mechanical forces imposed by the extracellular matrix (ECM) as SREBP1 regulators. The control of SREBP1 by mechanical cues depends on geranylgeranyl pyrophosphate, another key bio-product of the mevalonate pathway, and impacts on stem cell fate in mouse and on fat storage in Drosophila melanogaster.
Mechanistically, we show that activation of AMP-activated protein kinase (AMPK) by ECM stiffening and geranylgeranylated RhoA-dependent acto-myosin contraction inhibits SREBP1 maturation and functional activation. Our results unveil an unpredicted and evolutionary conserved role of SREBP1 in rewiring cell metabolism in response to mechanical cues.
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Oakley, Fredrick Daniel. „Biology of redox active endosomal signaling in response to Il-1-Beta“. Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1045.
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Interleukin-1-beta (IL-1β) is a potent proinflammatory cytokine. A primary outcome of IL-1β signaling is the activation of NFκB, a transcription factor that induces a large number of immune molecules, apoptotic factors, anti-apoptotic factors, and other transcription factors. Recent work has demonstrated that the activation of NFκB involves a multistep redox-signaling cascade that requires endocytosis of the interleukin receptor (IL-1R1)/ligand pair and superoxide production by NADPH oxidase 2 (Nox2) within the resulting newly formed early endosome. Hydrogen peroxide produced by the rapid dismutation of superoxide is necessary for the subsequent downstream recruitment of IL-1R1 effectors (TRAF6, IKK kinases) and ultimately the activation of NFκB. In this thesis, I have further dissected the spatial and temporal events that coordinate signaling processes of the IL-1β pathway. Using a combination of biophotonic imaging, immunofluorescence imaging, and lipid raft density gradient isolation, I demonstrate that both Nox2 and IL-1R1 are constitutively present in lipid raft microdomains on the plasma membrane. Stimulation by IL-1β induces endocytosis of Nox2 and IL-1R1 from the plasma membrane into caveolin-1, lipid raft positive early endosomes. Further, inhibition of lipid raft mediated endocytosis or deletion of caveolin-1 inhibits activation of NFκB, by IL-1β. We have also identified Vav1 as the Rac1 guanine exchange factor that is recruited to caveolin-1 positive lipid rafts following IL-1β stimulation, and demonstrated that dominant negative Vav1 inhibits NFκB activation by IL-1β. Following this work, I utilized assays for redox sensitivity and mass spectrometry to demonstrate that C70, C73, and C105 are hydrogen peroxide sensitive cysteines within the RING domain of TRAF6. I further demonstrate that hydrogen peroxide does not alter the E3 ubiquitin ligase activity associated with the TRAF6 RING domain. My findings suggest that the redox sensitivity of the RING domain mediates TRAF6 recruitment to the receptor complex. This is supported by the observation that hydrogen peroxide treatment of TRAF6, but not early signaling effectors (IL-1R1, IRAK1, IRAK4, MyD88) mediates TRAF6 recruitment to the IL-1 receptor complex. Further, mutation of the identified redox sensitive cysteines inhibits IL-1β signaling and NFκB activation. This research has helped to refine the understanding of the IL-1β signaling pathway, and may ultimately lead to new therapeutic targets for controlling inflammation.
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Searcy, James Lucas. „LIPID SIGNALING IN BRAIN AGING AND ALZHEIMER'S DISEASE: PHARMACOLOGICALLY TARGETING CHOLESTEROL SYNTHESIS, TRANSPORT AND METABOLISM“. Lexington, Ky. : [University of Kentucky Libraries], 2009. http://hdl.handle.net/10225/1147.
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Thesis (Ph. D.)--University of Kentucky, 2009.Title from document title page (viewed on May 12, 2010). Document formatted into pages; contains: xiv, 183 p. : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 158-177).
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Shrivastava, Shamit. „Non-linear solitary sound waves in lipid membranes and their possible role in biological signaling“. Thesis, Boston University, 2014. https://hdl.handle.net/2144/11049.
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Thesis (Ph. D.)--Boston UniversityBiological macromolecules self-assemble under entropic forces to form a dynamic 20 interfacial medium where the elastic properties arise from the curvature of the entropic potential of the interface. Elastic interfaces should be capable of propagating localized perturbations analogous to sound waves. However, (1) the existence and (2) the possible role of such waves in affecting biological functions remain unexplored. Both these aspects of "sound' as a signaling mechanism in biology are explored experimentally on mixed monolayers of lipids-fluorophores-proteins at the air/water interface as a model biological interface. This study shows - for the first time - that the nonlinear susceptibility near a thermodynamic transition in a lipid monolayer results in nonlinear solitary sound waves that are of 'all or none ' nature. The state dependence of the nonlinear propagation is characterized by studying the velocity-amplitude relationship and results on distance dependence, effect of geometry and collision of solitary waves are presented. Given that the lipid bilayers and real biological membranes have such nonlinearities in their susceptibility diagrams, similar solitary phenomenon should be expected in biological membranes. In fact the observed characteristics of solitary sound waves such as, their all or none nature, a biphasic pulse shape with a long tail and optp-mechano-electro-thermal coupling etc. are strikingly similar to the phenomenon of nerve pulse propagation as observed in single nerve fibers. Finally given the strong correlation between the activity of membrane bound enzymes and the susceptibility and the fact that the later varies within a single solitary pulse, a new thermodynamic basis for biological signaling is proposed. The state of the interface controls both the nature of sound propagation and its impact on incorporated enzymes and proteins. The proof of concept is demonstrated for acetylcholine esterase embedded in a lipid monolayer, where the enzyme is spatiotemporally "knocked out" by a propagating sound wave.
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Andrews, Shantaya Biunca, Timothy Audam und Dhirendra Dr Kumar. „Characterization of SIP470, A Plant Lipid Transfer Protein, and its Role in Plant Defense Signaling“. Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/44.
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Plants are resilient organisms that are continually evolving and continue to withstand an adverse and dynamic world. SABP2-interacting protein (SIP)-470 is a non-specific lipid transfer protein (nsLTP) that was identified in tobacco. SIP470 was discovered during a yeast two-hybrid screening with SABP2, which is an important methyl esterase enzyme which catalyzes the conversion of immobile MeSA into active salicylic acid (SA) during pathogenic challenge. SA activation and mobility allows for immunity to be carried to other, non-infected parts of the plant. This induced responses is called systemic acquired resistance (SAR) and it is a broad spectrum defense. Like many nsLTPs, SIP470 is small and has a predicted characteristic hydrophobic cavity. nsLTPs are found in higher plants and have repeatedly demonstrated protection in biotic stress including disease resistance, and greater resistance to both bacterial and fungal pathogens in overexpressed transgenic lines. This diverse class is also significantly involved in plant adaptation to environmental changes, namely drought, salinity, and freezing, but also in osmotic stress and wounding. Furthermore, nsLTPs are involved in wax metabolism and seed development. Subcellular localization of nsLTPs varies considerably during in vitro and in recent in vivo studies. SIP470 was originally identified in tobacco plants, and therefore, it is important to study its role directly in tobacco plants. SIP470 and eGFP fusion construct has been generated to study the subcellular localization of SIP470 in tobacco cells. SIP470 localization has shown a discontinuous, punctate arrangement around the membrane periphery which is being further verified by subcellular fractionation. Transgenic tobacco lines that are silenced in SIP470 via RNAi have been generated, and these plants are being screened. Overexpressor transgenic lines of SIP470 have been generated and are under the control of an estradiol-inducible promoter. These transgenic lines will be tested for their response in basal resistance and SAR.
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Cinque, A. „PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING“. Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/364862.
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Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant tumor of the central nervous system in adults. Despite decades of experimentation to improve the outcome of patients with GBM, this type of neoplasm remains one of the most lethal human cancers.Therefore, the need to test different and new agents for efficacy and safety is urgent. Perifosine (PF) is a synthetic lipid analogue belonging to a relatively new class of structurally related antitumor agents: the alkylphospholipids (APLs). PF exhibits potent antineoplastic activity against a multitude of cancer cell lines and different tumor models and is currently being tested in phase II clinical trial against major human tumors. However, the effect of PF against gliomas is poorly investigated. PF can induce apoptosis and/or cell growth arrest in tumor cells, but the details of its molecular mechanism is still to be elucidated. To date, the Ser/Thr kinase Akt, which is a key regulator of multiple survival pathways, is considered as the most important molecular target of PF.
However, PF can induce also Akt-independent effects and the contribution of Akt inhibition to the clinical activity of PF remains to be assessed. As other ALPs, PF may alter the structure and function of cell membranes directly by inducing a biophysical disturbance of cell membranes where it accumulates and/or indirectly by interfering with the metabolism and transport of membrane lipids. In particular, alterations in the properties of lipid rafts, ordered membrane lipid domains enriched in cholesterol and sphingolipids (SLs), could affect numerous signaling pathways crucial to cell survival and proliferation that are dependent on these structures.
On these premises, the purpose of this study was to investigate the sensitivity of GBM cells to PF treatment and to provide a contribution to the understanding of its molecular mechanism by focusing on the ability of PF to target membrane lipid metabolism and content, and, as a consequence, membrane-related signaling pathways crucial in the regulation of cell demise.
At first, we evaluated the effect of PF on cell survival in several human GBM cell lines. We demonstrated that in these cell lines PF inhibits cell viability in a dose-dependent manner and that its cytotoxic effects are not solely due to Akt inhibition. Furthermore, we found that in glioma cells PF maintains ERK in its phosphorylated/active state in a sustained manner over time. Treatment with the MAPK inhibitor PD98059 potentiates PF toxicity, and strongly reduces PF-induced LC3B-II increase. This could thus represent a molecular mechanism for self-defense from PF, at least in part due to the induction of protective autophagy. Moreover, in cells exposed to PF we found a time-dependent increase in the number of giant and multinucleated cells with an irregular shape, these morphological changes resembling those described for mitotic catastrophe, suggesting that this could be the mechanism of PF-induced cells death, while apoptosis was undetectable.
Accumulating literature indicates that in several tumor cell lines PF inhibits the rate limiting step of phosphatidylcholine (PC) synthesis, which is catalyzed by CTP:phosphocholine cytidylyltransferase, and this was associated to cell death with still unclear mechanisms. Furthermore, PC is the donor of phosphocholine in the reaction catalyzed by the enzyme sphingomyelin synthase (SMS), so the inhibition of the PC biosynthesis may also affect the sphingomyelin (SM) biosynthesis from ceramide (Cer). We found that also in GBM cells PF affects PC biosynthesis. In addition, in our model PF inhibits SM biosynthesis by affecting SMS activity, and the reduced PC seems not to represent a limiting factor for SM synthesis. The decreased utilization of Cer for SM biosynthesis results in a modest increase of Cer, which can accumulate at the endoplasmic reticulum (ER). Therefore, both the increased Cer levels, both the inhibition of PC synthesis in the ER could trigger ER stress ultimately leading to cell death. However, it is known from literature that in our GBM cells model PF fails to provoke ER stress, suggesting that other aspects of membrane lipid homeostasis, such as that involved in membrane functionality, are most probably involved in PF-induced cell death. Indeed, PC is the most abundant phospholipid in eukaryotic cellular membranes, essential for new membrane formation. On the other hand, SM together with glycosphingolipids (GSLs) represent the major SLs of the plasma membrane, displaying an asymmetric or polarized distribution, and play important roles in the regulation of membrane fluidity and sub-domain structures involved in cell signaling.
We demonstrated that PF affected the endogenous levels of phospholipids (PLs), inducing a decrease in the total PLs/protein ratio accompanied by a change in the PLs pattern. PF-treated cells were poorer in PC, SM, and phosphatidylserine (PS), and richer in phosphatidylethanolamine (PE). In addition, PF induces an about 60% increase of endogenous gangliosides content compared to untreated cells.
The dramatic changes in PLs and SLs endogenous content induced by PF could significantly affect membrane composition and functionality, which in turn can be involved in the biological response of cells to PF treatment. Indeed, we found that the inhibition of SM synthesis mimicked and potentiate PF cytotoxic effects; in addition the inhibition of gangliosides biosynthesis reverses cytotoxic action of PF thus suggesting that increase of gangliosides content is essential for its cytotoxic action.
In conclusion, PF treatment in GBM cells results in a complex network of effects where the alteration of the metabolism and content of membrane-lipid components (and maybe their related secondary messengers), seems to play a key role in determining cell death.
This study indicates that PF is decisive in its target to fight GBM cells, this representing a critical push to study new aspects in its cellular mechanisms, implying PF as anti-GBM agent.
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Homan, Edwin. „Discovery of Novel Lipid Pathways associated with the Metabolic Syndrome“. Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10343.
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The prevalence of obesity and type 2 diabetes has increased at alarming rates in recent decades. These diseases are prominent components of the metabolic syndrome, which is characterized by marked dyslipidemia. Adipose tissue contributes to the development of obesity-related diabetes through increased release of hormones and non-esterified fatty acids. The development of sensitive analytical tools for the broad detection of lipid biomolecules, such as liquid chromatographymass spectrometry (LC-MS), has spurred interest in the molecular determinants of the metabolic syndrome. The development of mature adipocytes from precursor fibroblasts—adipogenesis—plays a crucial role in the expansion of adipose tissue in obesity. We profiled differentiating 3T3-L1 pre-adipocytes by LC-MS and found that a class of monoglyceride lipids, monoalkylglycerol ethers (MAGEs), was transiently elevated early in adipogenesis. Upon addition to differentiating cells, MAGE specifically promoted adipocyte maturation and expression of adipogenic gene markers, indicating that MAGEs may be signaling molecules during adipogenesis. The insulin-sensitive glucose transporter, GLUT4, is downregulated during obesity and diabetes. In collaboration with Prof. Barbara Kahn, we studied a transgenic mouse model that overexpressed GLUT4 specifically in adipose tissue (AG4OX) and was protected from developing diabetes. We used LC-MS-based metabolomics to discover a previously undescribed class of bioactive lipids that was highly upregulated in AG4OX adipose tissue. We structurally characterized these lipids as fatty acyl hydroxy fatty acids (FAHFAs) and several positional isomers were chemically synthesized to confirm structural assignments via coelution studies. We discovered that individual FAHFAs, such as 5-palmitoyl-hydroxystearic acid (5-PAHSA), were differentially regulated by the transcription factor ChREBP. Circulating 5-PAHSA levels in mice and humans correlated with ChREBP expression and insulin resistance. In order to explore the biochemical regulation of FAHFAs, we developed an LCMS-based assay to measure FAHFA hydrolysis activity. We identified one enzyme, carboxyl ester lipase (CEL), as the major FAHFA hydrolase in pancreas, where the activity was highest. We confirmed its relevance in vivo by feeding labeled FAHFA to CEL inhibitor-treated mice. In this work we used LC-MS-based metabolomics to discover two lipids, MAGE and FAHFA, along with the CEL pathway, that may help us to better understand the pathogenesis of obesity and diabetes.Chemistry and Chemical Biology
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Filho, Edismauro Garcia Freitas. „O papel de gangliosídeos específicos como moduladores da liberação de mediadores de mastócitos“. Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17136/tde-21052015-180820/.
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Os mastócitos são células multifuncionais do sistema imunológico que participam em diversos processos biológicos. As funções dos mastócitos estão diretamente relacionados com a sua ativação e, subsequente, liberação de mediadores químicos. Os eventos iniciais da ativação dos mastócitos e da transdução de sinais ocorrem em microdomínios lipídicos (lipid rafts) da membrana plasmática. Os gangliosídeos derivados do GD1b são constituintes dos lipid rafts de mastócitos de roedores. O intercruzamento destes gangliosídeos pelo mAb AA4, resulta na formação de agregados (caps) na superfície celular e promove uma ativação parcial dos mastócitos, sem que ocorra a desgranulação. A ativação é semelhante a observada quando os FcRIs são intercruzados por antígenos multivalentes ligados a IgEs, mas neste caso ocorre a desgranulação. O presente estudo tem como objetivo caracterizar o papel dos gangliosídeos derivados do GD1b na liberação de mediadores de mastócitos da linhagem RBL-2H3. O intercruzamento dos gangliosídeos derivados do GD1b resulta na ativação dos fatores de transcrição NFAT e NFB e esta ativação é mediada pela proteína quinase Syk. A ativação destes fatores de transcrição resulta na liberação de mediadores neo-sintetizados, tais como: TNF-, interleucina (IL)-4. Por outro lado, o intercruzamento dos gangliosídeos derivados de GD1b não induz a liberação dos mediadores neoformados como o leucotrieno B4 (LTB4) e o leucotrieno C4 (LTC4). A agregação dos gangliosídeos derivados do GD1b resulta na desorganização dos lipid rafts e na redistribuição de seus componentes, como demostrado pela análise proteômica. Estes dados mostraram proteínas capazes de desencadear uma ativação parcial dos mastócitos e proteínas reguladoras negativas da desgranulação estão up reguladas, enquanto que proteínas críticas para a transdução do sinal estão down reguladas. Os resultados obtidos neste trabalho demonstram que os gangliosídeos derivados do GD1b desempenham papel crucial na integridade dos lipid rafts modulando a ativação e liberação de mediadores de mastócitos.Mast cells are immunoregulatory cells that participate in diverse biological events. The action of mast cells is directly related to their activation and subsequent mediator release. Early signal transduction events occur in lipid rafts in the plasma membrane. GD1b-derived gangliosides are known constituents of lipid rafts in rodent mast cells. The cross-linking of these gangliosides by mAb AA4 results in a partial activation of mast cells similar to that observed when FcRIs are cross-linked, but does not result in the mast cell degranulation. With time, the gangliosides bound to mAb AA4 cap on the cell surface. The present study aims to characterize the role of the rodent mast cell specific gangliosides derived from GD1b in mediator release from RBL-2H3 mast cells. Cross-linking the GD1b-derived gangliosides activated the transcription factors NFAT and NFB and this activation was mediated by Syk. The activation of theses transcription factors by cross-linked GD1b-derived gangliosides results in the release of the neo-synthesized mediators TNF- and interleukin (IL)-4. However, cross-linking GD1b-derived gangliosides did not stimulate release of the newly formed mediators leukotriene B4 (LTB4) and leukotriene C4 (LTC4). Capping of GD1b-derived gangliosides disorganized lipid rafts and resulted in a redistribution of lipid raft components. Proteomic analysis showed that proteins that trigger mast cell activation and negative regulatory proteins of degranulation are up regulated, whereas proteins critical for signal transduction are down regulated in mast cells where the gangliosides are capped. The results of this work demonstrate that the mast cell-specific GD1b-derived gangliosides are crucial in maintaining the functional integrity of the lipid rafts and modulate cell activation and subsequent mediator release from mast cells.
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Dian, Emese Emöke. „Application of Cultured Neuronal Networks for Use as Biological Sensors in Water Toxicology and Lipid Signaling“. Thesis, University of North Texas, 2004. https://digital.library.unt.edu/ark:/67531/metadc5557/.
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This dissertation research explored the capabilities of neuronal networks grown on substrate integrated microelectrode arrays in vitro to be applied to toxicological research and lipid signaling. Chapter 1 details the effects of chlorine on neuronal network spontaneous electrical activity and pharmacological sensitivity. This study demonstrates that neuronal networks can maintain baseline spontaneous activity, and respond normally to pharmacological manipulations in the present of three times the chlorine present in drinking water. The findings suggest that neuronal networks may be used as biological sensors to monitor the quality of water and the presence of novel toxicants that cannot be detected by conventional sensors. Chapter 2 details the neuromodulatory effects of N-acylethanolamides (NAEs) on the spontaneous electrical activity of neuronal networks. NAEs are a group of lipids that can mimic the effects of marijuana and can be derived from a variety of plant sources including soy lecithin. The most prominent NAEs in soy lecithin, palmitoylethanolamide (PEA) and linoleoylethanolamide (LEA), were tested individually and were found to significantly inhibit neuronal spiking and bursting activity. These effects were potentiated by a mixture of NAEs as found in a HPLC enriched fraction from soy lecithin. Cannabinoid receptor-1 (CB1-R) antagonists and other cannabinoid pathway modulators indicated that the CB1-R was not directly involved in the effects of NAEs, but that enzymatic degradation and cellular uptake were more likely targets. The results demonstrate that neuronal networks may also be a viable platform for the elucidation of biochemical pathways and drug mechanisms of action.
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Audam, Timothy Ndagi. „Characterization of SIP470, a Family 1 Lipid Transfer Protein and its Role in Plant Stress Signaling“. Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3103.
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SIP470, a putative tobacco lipid transfer protein, was identified in a yeast two-hybrid screen to interact with SABP2. SABP2 is a critical role in SA-mediated signaling in tobacco and other plants. In vitro studies using purified recombinant SIP470 confirmed that it is a lipid binding protein. In an attempt to determine its role in mediating stress responses, Arabidopsis T-DNA insertion knockout lines lacking SIP470 homolog were used for the analysis. These mutant plants were defective in basal resistance against microbial pathogens. Expression of defense gene PR-1 was also delayed in these mutant plants. Interestingly, these mutant plants were not defective in inducing systemic acquired resistance. Besides biotic stress, these mutant plants also showed increased susceptibility to abiotic stresses. To directly study the role of SIP470 in tobacco plants, transgenic tobacco lines, with reduced levels of SIP470 expression, were generated using RNAi and transgenic lines overexpressing SIP470 were also generated.
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Desbourdes, Céline. „Nucléoside diphosphate kinase D : une protéine mitochondriale bifonctionnelle“. Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV004/document.
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Les nucléosides diphosphate kinases (NDPK) sont essentielles pour la génération des nucléosides triphosphates (NTPs) en utilisant l’ATP et des NDPs. L’isoforme mitochondriale de NDPK (NDPK-D), située dans l’espace intermembranaire des mitochondries, possède deux modes de fonctionnement. Dans le premier mode (« phosphotransfert »), la protéine a une activité de kinase comme les autres enzymes NDPK. Dans ce mode de fonctionnement, NDPK-D produit du GTP pour la protéine optique atrophy 1 (OPA1), une GTPase impliquée dans la fusion des mitochondries, et de l’ADP pour le translocateur à adénine (ANT) et l’ATPase mitochondriale pour la régénération d’ATP. Le second mode de fonctionnement est appelé « transfert de lipide » et est lié à la capacité de la protéine à se lier aux phospholipides anioniques, particulièrement la cardiolipine (CL). Dans ce mode NDPK-D peut réticuler les deux membranes mitochondriales et transférer CL de la membrane interne vers la membrane externe des mitochondries, pouvant servir de signal pour la mitophagie et l’apoptose. Ce travail a pour objectif d’étudier plus en détails ces différentes fonctions de NDPK-D. En utilisant des cellules HeLa exprimant de façon stable la protéine sauvage, kinase inactive (mutation H151N) ou incapable de se lier aux lipides (mutation R90D) et des cellules épithéliales de poumons de souris, nous montrons (i) une grande proximité entre NDPK-D et OPA1 qui conduit au channeling de GTP par NDPK-D pour OPA1, (ii) le rôle essentiel de NDPK-D pour l’externalisation de CL vers la surface des mitochondries pendant la mitophagie, servant de signal de reconnaissance pour le complexe LC3-II-autophagosomes afin d’éliminer les mitochondries endommagées, (iii) la possible inhibition de l’externalisation de CL par la présence de complexes NDPK-D/OPA1, et (iv) un phénotype pro-métastatique des cellules HeLa exprimant la NDPK-D mutée (H151N ou R90D), caractérisé par un fort potentiel invasif et migratoire, un profil protéique altéré, et des modifications au niveau structural et fonctionnel du réseau mitochondrial. Finalement, une première stratégie d’expression et de purification de la protéine OPA1 entière a été établie pour de futures études in vitro des complexes NDPK-D/OPA1The nucleoside diphosphate kinases (NDPK) are essential for generation of nucleoside triphosphates (NTPs) using ATP and NDPs. The mitochondrial NDPK isoform (NDPK-D) located in the mitochondrial intermembrane space is found to have two modes of function. First, the phosphotransfer mode in which the protein has a kinase activity like other NDPK enzymes. In this mode, NDPK-D produces GTP for the optic atrophy 1 protein (OPA1), a GTPase involved in mitochondrial fusion, and ADP for the adenylate translocator (ANT) and the mitochondrial ATPase for ATP regeneration. The second mode of function is called lipid transfer and is related to the capacity of NDPK-D to bind anionic phospholipids, especially cardiolipin (CL). In this mode, the protein can cross-link the two mitochondrial membranes and transfer CL from the inner to the outer mitochondrial membrane, which can serve as a signal for mitophagy and apoptosis. This work aims to study these NDPK-D functions in more detail. With the use of HeLa cells stably expressing the wild-type, kinase inactive (H151N mutation) or lipid binding deficient (R90D mutation) NDPK-D and mouse lung epithelial cells, we show (i) the close proximity between NDPK-D and OPA1 that leads to GTP channeling from NDPK-D to OPA1, (ii) the essential role of NDPK-D for CL externalization to the mitochondrial surface during mitophagy, serving as a recognition signal for LC3-II-autophagosomes to eliminate damaged mitochondria, (iii) the possible inhibition of CL externalization due to the presence of NDPK-D/OPA1 complexes, and (iv) a pro-metastatic phenotype of HeLa cells expressing either of the NDPK-D mutants (H151N or R90D), characterized by high invasive and migratory potential, altered proteomic profile and changed mitochondrial network structure and function. Finally, a first bacterial expression and purification strategy for full-length OPA1 has been established for future in vitro studies of NDPK-D/OPA1 complexes
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Kwong, Eric K. „The Role of Sphingosine Kinase 2 in Alcoholic Liver Disease“. VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5808.
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Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, the detailed mechanism(s) underlying ALD and disease progression is poorly understood. We have discovered that sphingosine kinase 2 (SphK2) deficient (SphK2-/-) mice on an alcohol diet exhibit increased steatosis and inflammation compared to wild type mice. Sphingosine 1-phosphate receptor 2 (S1PR2) and SphK2 have been previously shown to play a key role in nutrient metabolism and signaling. However, their roles in alcohol-induced liver injury have not been characterized.
The overall objective of this study is to determine the molecular mechanism(s) by which disruption of S1PR2-mediated SphK2 signaling contributes to ALD. The effects of alcohol on mouse primary hepatocytes and cultured RAW264.7 macrophages were examined. The acute on chronic alcohol mouse model from NIAAA that recapitulates the drinking pattern of human ALD patients was used to study the effects of SphK2 deficiency in ALD. In addition, 60-day chronic alcohol mouse model was used to determine whether a more severe form of ALD was present in SphK2-/- mice. The results indicated that SphK2-/- mice on an alcohol diet exhibited an increased amount of hepatic steatosis compared to wild type mice. Genes regulating lipid metabolism were also dysregulated in SphK2-/- mice. SphK2-/- mice also had increased inflammation and liver injury as shown by an upregulation of inflammatory markers and increased levels of liver enzymes. Moreover, SphK2 protein expression levels were downregulated in the human livers of alcoholic cirrhotic and hepatocellular carcinoma (HCC) patients. These findings contribute to a greater understanding of the pathophysiology of ALD and could provide information on the development of novel therapeutics against ALD.
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Mahammad, Saleemulla. „Cholesterol in T cells homeostasis, plasma membrane organization and signaling /“. Doctoral thesis, Stockholm : The Wenner-Gren Institute, Stockholm University, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-38357.
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Diss. (sammanfattning) Stockholm : Stockholms universitet, 2010.At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press.
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Goswami, Ishan. „Computational and Experimental Investigation of the Critical Behavior Observed in Cell Signaling Related to Electrically Perturbed Lipid Systems“. Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/97564.
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Problem Statement: The use of pulsed electric fields (PEFs) as a tumor treatment modality is receiving increased traction. A typical clinical procedure involves insertion of a pair of electrodes into the tumor and administration of PEFs (amplitude: ~1 kV/cm; pulse-width: 100 μs). This leaves a zone of complete cell death and a sub-lethal zone where a fraction of the cells survive. There is substantial evidence of an anti-tumor systemic immune profile in animal patients treated with PEFs. However, the mechanism behind such immune profile alterations remains unknown, and the effect of PEFs on cell signaling within sub-lethal zones remains largely unexplored. Moreover, different values of a PEF pulse parameter, for e.g. the pulse-widths of 100 μs and 100 ns, may have different effects on cell signaling. Thus, the challenge of answering the mechanistic questions is compounded by the large PEF parameter space consisting of different combinations of pulse-widths, amplitudes, and exposure times.
Intellectual merit: This Ph.D. research provides proof that sub-lethal PEFs can enhance anti-tumor signaling in triple negative breast cancer cells by abrogating thymic stromal lymphopoietin signaling and enhancing stimulatory proteins such as the tumor necrosis factor. Furthermore, experimental evidence produced during this Ph.D. research demonstrates that PEFs may not directly impact the intracellular mitochondrial membrane at clinically relevant field amplitudes. As demonstrated in this work, PEFs may influence the mitochondria via an indirect route such as disruption of the actin cytoskeleton and/or alteration of ionic environment in the cytoplasm due to cell membrane permeabilization. Thus, a reductionist approach to understanding the influence of PEFs on cell signaling is proposed by limiting the study to membrane dynamics. To overcome the problem of investigating the entire PEF parameter space, this Ph.D. research proposes a first-principle thermodynamic approach of scaling the PEF parameter space such that an understanding developed in one regime of PEF pulse parameter values can be used to understand other regimes of the parameter space. Demonstration of the validity of this scaling model is provided by coupling Monte-Carlo methods for density-of-states with the steepest-entropy-ascent quantum thermodynamic framework for the non-equilibrium prediction of the lipid membrane dynamics.Ph. D.
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Panakova, Daniela. „Lipoprotein particles associate with lipid-linked proteins and are required for long-range Wingless and Hedgehog signaling“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2005. http://nbn-resolving.de/urn:nbn:de:swb:14-1122025765300-27455.
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Morphogens of the Wnt and Hedgehog families are secreted signaling molecules that coordinate growth and patterning of many different tissues. Both, Wingless and Hedgehog spread across long distances in developing wing of Drosophila melanogaster. However, both proteins are covalently modified with lipid moieties. The mechanisms that allow long-range movement of such hydrophobic molecules are unclear. Like Wingles and Hedgehog, glycosylphosphatidylinositol (gpi)-linked proteins also transfer between cells with their lipid anchor intact. It has been speculated that gpi-linked proteins and lipid-linked morphogens travel together on a membranous particle, which was termed an argosome. As yet however, no functional link between argosome production and dispersal of lipid-linked proteins has been established. The topic of this thesis is to understand the cell biological nature of the argosome and thus contribute to understanding of morphogen gradient formation. To address the question of argosome biosynthesis, at least two models have been proposed. One possibility is that argosomes are membranous exovesicles with a complete membrane bilayer. Alternatively, argosomes might resemble lipoprotein particles that comprise on of a family of apolipoproteins scaffolded around a phospholipid monolayer that surrounds a core of esterified cholesterol and triglyceride. Lipid-modified proteins of the exoplasmic face of the membrane (like GFPgpi, Wingless or Hedgehog) might fit well into the outer phospholipid monolayer of such a particle. Here, I utilize biochemical fractionation to determine the sort of particle that lipid-linked proteins associate with. I show that Wingless, Hedgehog and gpi-linked proteins bind Drosophila lipoprotein particles in vitro, and colocalize with them in wing imaginal discs. Next, I use genetic means to address the functional importance of this association. I demonstrate that reducing Lipophorin levels in Drosophila larvae perturbs long-range but not shor-range Wingless and Hedgehog signaling, and increases the sequestration of Hedgehog by Patched. I propose that Lipophorin particles are vehicles for the long-range movement of lipid-linked morphogens and gpi-linked proteins.
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Klose, Jana. „The role of lipid signaling and metabolism in morphogenesis and pathogenesis of the fungal pathogen Ustilago maydis“. Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31085.
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The phytopathogenic fungus Ustilago maydis is obligately dependent on infection of maize to complete the sexual phase of its life cycle. Mating interactions between budding cells establish an infectious filamentous cell type that invades the host, induces tumors, and forms teliospores. The yeast-to-filamentous morphological transition is regulated by cAMP and MAPK signaling pathways known to control the pathogenic development in the host. The signals influencing this transition during infection have not yet been identified. In this study, we demonstrated that lipids triggered the dimorphic switch to promote a filamentous phenotype resembling the infectious filaments found in planta, which was dependent on cAMP and Ras/MAPK signaling. In addition, low levels of lipids (4nM) induced the response suggesting that they are acting as ligands to trigger the morphological change. Overall, lipids may represent one of the signals that promotes and maintains filamentation of the fungus in the host.
To explore potential metabolic and signaling roles of lipids in morphogenesis and pathogenesis, we deleted genes encoding enzymes in the β-oxidation of fatty acids (mfe2, peroxisomal multifunctional enzyme; had1, mitochondrial 3-hydroxyacyl-CoA dehydrogenase) and a phospholipase A2 (lip2). Loss of mfe2 blocked extensive proliferation of fungal filaments in planta, delayed sporulation and reduced virulence. Loss of had1 resulted in attenuation of disease symptoms and impaired teliospore germination. These findings suggest that mitochondrial P-oxidation may be crucial during teliospore germination and initial stages of in planta fungal development, and that peroxisomal β-oxidation may be required during later stages of in planta development. In addition, Mfe2 and Had1 were specifically required for the filamentation induced by linoleic and myristic acid, respectively. Overall, lipids represent an important carbon source during biotrophic growth, and lipid utilization by U. maydis may influence additional aspects of infection (i.e., signal perception or host defense). Loss of lip2 resulted in more severe symptom development and more rapid teliospore maturation during infection. The Lip2 function might be important during fungus-host interactions to limit premature development of disease symptoms prior to sporulation. In summary, this work contributes to the emerging idea that lipid metabolism and signaling are important for biotrophic interactions between plants and fungal pathogens.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Efe, Jem A. „Vacuole biogenesis, function, and size control in S. cerevisiae central roles for membrane trafficking and lipid signaling /“. Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3292284.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed October 8, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 166-184).
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Krothapalli, Kartikeya. „Association of plastid lipid metabolism with the activation of systemic acquired resistance in Arabidopsis thaliana“. Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/1058.
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Newton, Hannah S. „Potassium channels and adenosine signaling in T cells of head and neck cancer patients“. University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603713656776019.
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Mandal, Mihir Kumar. „MOLECULAR AND BIOCHEMICAL CHARACTERIZATION OF OLEATE- AND GLYCEROL-3-PHOSPHATE-REGULATED SIGNALING IN PLANTS“. UKnowledge, 2012. http://uknowledge.uky.edu/plantpath_etds/3.
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Oleic acid (18:1), a monounsaturated fatty acid (FA), is synthesized upon desaturation of stearic acid (18:0) and this reaction is catalyzed by the plastidal enzyme stearoyl-acyl carrier protein-desaturase (SACPD). A mutation in the SSI2/FAB2 encoded SACPD lowers 18:1 levels, which correlates with induction of various resistance (R) genes and increased resistance to pathogens. Genetic and molecular studies have identified several suppressors of ssi2 which restore altered defense signaling either by normalizing 18:1 levels or by affecting function(s) of a downstream component. Characterization of one such ssi2 suppressor mutant showed that it is required downstream of low 18:1-mediated constitutive signaling and partially restores altered defense signaling in the ssi2 mutant. Molecular and genetic studies showed that the second site mutation was in the Nitric Oxide Associated (NOA) 1 gene, which is thought to participate in NO biosynthesis. Consistent with this result, ssi2 plants accumulated high levels of NO and showed an altered transcriptional profile of NO-responsive genes. Interestingly, the partial defense phenotypes observed in ssi2 noa1 plants were completely restored by an additional mutation in either of the two nitrate reductases NIA1 or NIA2. This suggested that NOA1 and NIA proteins participated in NO biosynthesis in an additive manner. Biochemical studies showed that 18:1 physically bound NOA1, in turn leading to its degradation in a protease-dependent manner. In concurrence, overexpression of NOA1 did not promote NO-derived defense signaling in wild-type plants unless 18:1 levels were lowered. Subcellular localization showed that NOA1 and the 18:1-synthesizing SSI2 were present in close proximity within the nucleoids of chloroplasts. Indeed, pathogen- or low 18:1- induced accumulation of NO was primarily detected in the chloroplasts and their nucleoids. Together, these data suggested that 18:1 levels regulate NO synthesis and thereby NO-mediated retrograde signaling between the nucleoids and the nucleus. Since cellular pools of glycerol-3-phosphate (G3P) regulate 18:1 levels, I next analyzed the relationship between G3P and 18:1. Interestingly, unlike 18:1, an increased G3P pool was associated with enhanced systemic immunity in Arabidopsis. This was consistent with G3P-mediated transcriptional reprogramming in the distal tissues. To determine mechanism(s) underlying G3P-conferred systemic immunity, I analyzed the interaction between G3P and a lipid transfer protein (LTP), DIR1. In addition, I monitored localization of DIR1 in both Arabidopsis as well as tobacco. Contrary to its predicted apoplastic localization, DIR1 localized to endoplasmic reticulum and plasmodesmata. The symplastic localization of DIR1 was confirmed using several different assays, including co-localization with plasmodesmatal-localizing protein, plasmolysis and protoplast-based assays. Translocation assays showed that G3P increased DIR1 levels and translocated DIR1 to distal tissues. Together, these results showed that G3P and DIR1 are present in the symplast and their coordinated transport into distal tissues is likely essential for systemic immunity.
In conclusion, this work showed that low 18:1-mediated signaling is mediated via NO, synthesis of which is likely initiated in the plastidal nucleoids. In addition, my work shows that G3P functions as an independent signal during systemic signaling by mediating translocation of the lipid transfer protein, DIR1.
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Paquette, Sara Montminy. „Evasion of LPS-TLR4 Signaling as a Virulence Determinate for Yersinia pestis“. eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/458.
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Yersinia pestis, the gram-negative causative agent of plague, is a master of immune evasion. The bacterium possesses a type three secretion system which translocates Yop effector proteins into host immune cells to inhibit a number of immune and cell signaling cascades. Interestingly, this apparatus is not expressed at low temperatures such as those found within the flea vector and is therefore neither in place nor functional when the bacteria are first transmitted into a mammalian host. However, the bacterium is still able to avoid activating the immune system, even very early during infection.
When grown at 37°C (human body temperature) Y. pestis produces a tetra-acyl lipid A molecule, which is antagonistic to the human Toll like receptor 4/MD2, the major lipopolysaccharide recognition receptor. Although tetra-acyl lipid A binds this receptor complex, it does not induce signaling, and in fact inhibits the receptors interaction with other stimulatory forms of lipid A. The work undertaken in this thesis seeks to determine if the production of tetra-acyl lipid A by Y. pestis is a key virulence determinant and was a critical factor in the evolution of Y. pestis from its ancestral parent Yersinia pseudotuberculosis.
By examining the enzymes involved in the lipid A biosynthesis pathway, it has been determined that Y. pestis lacks LpxL, a key enzyme that adds a secondary acyl chain on to the tetra acyl lipid A molecule. In the absence of this enzyme, Y. pestis cannot produce a TLR4 stimulating form of lipid A, whereas Y. pseudotuberculosis does contain the gene for LpxL and produces a stimulatory hexa acyl lipid A. To determine if the absence of LpxL in Y. pestis is important for virulence, LpxL from E. coli and Y. pseudotuberculosis were introduced into Y. pestis. In both cases the addition of LpxL led to bacterium which produced a hexa-acylated lipid A molecule and TLR4/MD2 stimulatory LPS. To verify the LpxL phenotype, lpxL was deleted from Y. pseudotuberculosis, resulting in bacteria which produce tetra-acylated lipid A and nonstimulatory LPS. Mice challenged with LpxL expressing Y. pestis were found to be completely resistant to infection. This profound attenuation in virulence is TLR4 dependent, as mice deficient for this receptor rapidly succumb to disease. These altered strains of the bacterium also act as vaccines, as mice infected with Y. pestis expressing LpxL then challenged with wild type Y. pestis do not become ill. These data demonstrate that the production of tetra-acyl lipid A is a critical virulence determinant for Y. pestis, and that the loss of LpxL formed a major step in the evolution of Y. pestis from Y. pseudotuberculosis.
These bacterial strains were also used as tools to determine the contributions of different innate immune receptors and adaptor molecules to the host response during Y. pestis infection. The use of LpxL expressing Y. pestis allowed identification of the innate immune pathways critical for protection during Y. pestis infection. This model also established that CD14 recognition of rough LPS is critical for protection from Y. pestisexpressing LpxL, and activation of the IL-1 receptor and the induction of IL-1β plays a major role in this infection as well.
The lipid A acylation profile of gram negative bacteria can have a direct and profound effect on the pathogenesis of the organism. This work illustrates a previously unknown and critical aspect of Y. pestis pathogenesis, which can be extended to other gram-negative pathogens. The greater detail of the contributions which different host adaptor and receptor molecules make to the overall innate immune signaling pathway will allow a better insight into how gram negative infections progress and how they are counteracted by the immune system. Alterations of the lipid A profile of Y. pestis have important implications for the production of vaccines to Y. pestis and other gram negative pathogens. Taken together, this work describes a novel mechanism for immune evasion by gram negative bacteria with consequences for understanding the immune response and the creation of more effective vaccines, both of which will decrease the danger posed by this virulent pathogen.
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Hodson, Jane E. „Tobacco Phospholipase D β1: Molecular Cloning and Biochemical Characterization“. Thesis, University of North Texas, 2002. https://digital.library.unt.edu/ark:/67531/metadc3341/.
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Transgenic tobacco plants were developed containing a partial PLD clone in antisense orientation. The PLD isoform targeted by the insertion was identified. A PLD clone was isolated from a cDNA library using the partial PLD as a probe: Nt10B1 shares 92% identity with PLDβ1 from tomato but lacks the C2 domain. PCR analysis confirmed insertion of the antisense fragment into the plants: three introns distinguished the endogenous gene from the transgene. PLD activity was assayed in leaf homogenates in PLDβ/g conditions. When phosphatidylcholine was utilized as a substrate, no significant difference in transphosphatidylation activity was observed. However, there was a reduction in NAPE hydrolysis in extracts of two transgenic plants. In one of these, a reduction in elicitor- induced PAL expression was also observed.
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Buscató, Arsequell Estel·la [Verfasser], Ewgenij [Akademischer Betreuer] Proschak und Dieter [Akademischer Betreuer] Steinhilber. „Synthesis and in vitro evaluation of lipid signaling modulators / Estella Buscató Arsequell. Gutachter: Dieter Steinhilber ; Ewgenij Proschak. Betreuer: Ewgenij Proschak“. Frankfurt am Main : Univ.-Bibliothek Frankfurt am Main, 2013. http://d-nb.info/1046622684/34.
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Mahon, Robert Norman III. „Direct Inhibition of CD4+ T-cell Activation by Mycobacterium tuberculosis Cell Wall Glycolipids“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1275668686.
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Yu, Lingli. „Nerve Growth Factor Signaling from Membrane Microdomain to Nucleus : Differential Regulation by Caveolins“. Phd thesis, Ecole normale supérieure de lyon - ENS LYON, 2012. http://tel.archives-ouvertes.fr/tel-00796393.
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At the plasma membrane, both NGF receptors have been shown to localized to lipid rafts, specific subdomains that are enriched in cholesterol, sphingolipids and the presence of caveolin proteins (Cav1 and/or Cav2). The focus of this work is on this membrane microenvironment mediated modulation of NGF signaling which via two receptors: p75NTR and TrkA. In the present work we found that overexpression of Cav-1 in mouse dorsal root ganglia neurons significantly impacted neurite extension. Similarly, overexpression of Cav-1 in PC12 cells strongly inhibits their ability to grow neurites in response to NGF. It inhibits NGF signaling without, impairing transient MAPK pathway activation. Rather, it does so by sequestering NGF receptors in lipid rafts, which correlates with the cell surface localization of downstream effectors, and phosphorylated-Rsk2, resulting in the prevention of the phosphorylation of CREB. By contrast, overexpression of Cav-2 potentiates NGF induced differentiation, which is accompanied by sustained activation of downstream effectors, and standard internalization of the receptors. This differential effect could be due to the different localization of Caveolins, that modifies the microenvironment, thereby affecting NGF signaling. Furthermore, PC12 cells expressing the non-phosphorylatable Cav-1 mutant (S80V), neither TrkA trafficking or CREB phosphorylation are inhibited and the response resembles that observed in Cav-2 expressing PC12 cells. These studies underline the interplay between caveolins and NGF signalling, offering insight into the potential impact of Caveolin-1 and mutations thereof in certain cancers where NGF signaling is involved.
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Wehmeyer, Lance. „Investigating crosstalk in lipid rafts between the glucocorticoid receptor and gonadotropin-releasing hormone receptor signaling pathways in a gonadotrope cell line“. Master's thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/11346.
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Includes abstract.Includes bibliographical references (leaves 121-158).
A recent study from the Hapgood laboratory demonstrated the presence of a novel crosstalk mechanism between the glucocorticoid receptor (GR) and gonadotropin-releasing hormone receptor (GnRHR), indicating an additional direct mechanism for the effects of stress on reproduction. The present study investigated whether this crosstalk between the GR and GnRHR involves the co-localization of these receptors to lipid rafts, providing a specialized distinct region where the receptors can be in close proximity and reciprocally modulate each other’s signaling pathways.
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Gorjão, Renata. „Efeito dos ácidos graxos sobre a via de sinalização da interleucina-2 em linfócitos humanos“. Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-15092008-134403/.
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Neste estudo investigamos os efeitos dos ácidos graxos sobre a função e sinalização intracelular de linfócitos humanos. Os ácidos oléico (OA) e linoléico (LA), em baixas concentrações, estimularam a proliferação celular induzida pela IL-2 através do aumento da fosforilação da proteína PKC-Z que levou a um aumento da fosforilação de ERK 1/2. Já os ácidos palmítico (PA), esteárico (SA), DHA e EPA diminuíram a proliferação destas células e inibiram a fosforilação de JAK1 e 3, STAT5, ERK e Akt. Os resultados obtidos são sugestivos de que o efeito inibitório promovido por PA, SA, DHA e EPA sobre a proliferação de linfócitos ocorreu devido à diminuição da fosforilação de proteínas fundamentais para a proliferação celular. Por outro lado, OA e LA estimularam a proliferação de linfócitos aumentando a fosforilação de ERK 1/2 através da ativação de PKC-Z, efeito dependente da PI3K. O efeito inibitório promovido pelo DHA está associado a uma alteração na quantidade de lipid rafts na membrana plasmática nos quais o receptor de IL-2 está localizado.The effect of fatty acids (FA) on interleukin -2 (IL-2) signaling pathway in human lymphocytes was investigated. Docosahexaenoic (DHA), eicosapentaenoic (EPA), palmitic (PA) and stearic (SA) acids decreased lymphocyte proliferation in concentrations above 50 mM. However, oleic (OA) and linoleic (LA) acids increase lymphocyte proliferation at 25 mM. PA, SA, DHA and EPA decreased JAK 1, JAK 3, STAT 5 and AKT phosphorylation induced by IL-2 but OA and LA did not cause any effect. OA and LA increased ERK1/2 phosphorylation whereas the other FA caused a marked decrease. PKC-Z phosphorylation was decreased by OA and LA only. In conclusion, the inhibitory effect of PA, SA, DHA and EPA on lymphocyte proliferation observed in our previous study was due to a decrease in protein phosphorylation activated by IL-2. Probably, OA and LA stimulated lymphocyte proliferation by increasing ERK 1/2 phosphorylation throught PKC-Z activation. The inhibition of JAK 1, JAK3, STAT 5, ERK1/2 and Akt phosphorylation caused by DHA is associated to a decrease in membrane lipid rafts contend.
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Paulino, Rachel Santini. „Estresse oxidativo de duas espécies de macrófitas aquáticas em diferentes condições ambientais em um estuário de região neotropical“. Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/153368.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
O estresse oxidativo causado pela produção de espécies reativas de oxigênio (EROs) é uma das respostas que as plantas apresentam frente a um estresse ambiental. Nosso objetivo foi avaliar o estresse oxidativo das macrófitas aquáticas Crinum americanum e Spartina alterniflora em duas condições: salinidade e nutrientes que ocorrem no estuário do rio Itanhaém (SP). Raízes e folhas (5 plantas) de C. americanum foram coletadas em cada área (5 amostras/área). O material vegetal para análises de clorofila (a+b), carotenóides, peróxido de hidrogênio (H2O2), malonaldeído (MDA) e enzimas antioxidantes SOD e CAT foram acondicionado em N2 líquido no campo e posteriormente armazenado em freezer a -80 °C. Também foram coletados em cada réplica material vegetal para avaliar o teor de N e P totais da planta e do sedimento Os dados obtidos foram submetidos à Análise de Variância (ANOVA) e comparados pelo teste de Tukey (p < 0,05). Os resultados obtidos mostraram que: C. americanum e S. alterniflora sofreram maior estresse oxidativo em alto e médio estuário, respectivamente; Os indivíduos de S. alterniflora sofreram maior estresse na área de lançamento de esgoto.
The oxidative stress caused by the production of reactive oxygen species (ROS) is one of the responses that plants exhibit facing environmental stress. Our objective was to evaluate the oxidative stress of the aquatic macrophytes Crinum americanum and Spartina alterniflora under two conditions: salinity and nutrients that occur in the estuary of the Itanhaém river (SP). Roots and leaves (5 plants) of C. americanum were collected in each area (5 samples / area). The plant material for analysis of chlorophyll (a + b), carotenoids, H2O2, MDA and antioxidant enzymes SOD and CAT with platform in N2 without field and liquid in freezer at -80 ° C. Vegetable material was also collected in each replicate to evaluate the total N and P content of the plant and of the sediment. The data were submitted to Analysis of Variance (ANOVA) and compared by the Tukey test (p <0.05). The results showed that: C. americanum and S. alterniflora suffered higher oxidative stress in upper and middle estuary, respectively; The State of São Paulo changes have suffered greater stress in the area of sewage
2018SLR05032
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Lajoie, Patrick. „Regulation of receptor signaling and membrane trafficking by beta1,6-branched n-glycans and caveolin-1/cholesterol membrane domain organization“. Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/336.
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Modification by glycosylation gives proteins a range of diverse functions reflecting their structural variability. N-glycans regulate many biological outcomes in mammalian cells under both normal and pathological conditions. They play a major role in various pathologies such as cancer and lysosomal storage diseases. Interplay between N-glycans and other regulators, such as membrane lipid domains, in the control of signaling pathways remains poorly understood. My thesis therefore focuses on how N-glycans and membrane lipid domains oppose and/or work together at different cellular levels to regulate various processes such as receptor signaling and diffusion, endocytosis and lysosomal organelle biogenesis.
Mgat5 encodes for ß1,6-N-acetylglucosaminyltransferase V that produces N-glycans, the preferred ligand for galectins. In tumor cells, galectins bind glycosylated receptors at the cell surface forming a lattice, that restricts receptor endocytosis and enhances its residency at the plasma membrane. In the first part of my thesis, I report that Galectin/receptor crosslinking opposes receptor sequestration by oligomerized caveolin-1 (Cav1) domains overriding its negative regulation of epidermal growth factor receptor (EGFR) signaling, cell surface diffusion and tumor growth. These results identify Cav1 as a conditional tumor suppressor.
I also demonstrate that Cav1 is a negative regulator of lipid raft-mediated endocytosis. Cav1 indirectly regulates the internalization of cholera toxin b subunit to the Golgi apparatus independently of caveolae formation. That identifies a new role for caveolin-1 outside caveolae in the regulation of raft-dependent endocytosis
Finally, Mgat5 overexpression in pneumocytes is associated with the expression of a lysosomal organelle, the multilamellar body (MLB), via autophagy. MLB expression is also a characteristic of various lysosomal storage diseases. I demonstrate that cholesterol accumulation can override the need for Mgat5 overexpression in MLB formation indicating that they may form via multiple mechanisms. However, I also demonstrate that a contribution of the autophagic pathway is a common determinant of biogenesis of MLB of various lipid compositions.
In conclusion, Mgat5-dependent protein glycosylation and Cav1/raft domains therefore both function as regulators of plasma membrane interactions, endocytosis and lysosomal organelle biogenesis. Understanding of this interplay is crucial for the understanding of the mechanisms involve in various pathologies such as cancer and lysosomal storage diseases.
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Tiwari, Vijay. „Isolation and Heterologous Expression of Putative Tomato Fatty Acid Amide Hydrolase“. Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3138.
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N-acylethanolamines (NAEs) are derived from a minor membrane lipid constituent N-acylphosphatidylethanolamine and are hydrolyzed by fatty acid amide hydrolases (FAAH) into free fatty acid (FFA) and ethanolamine in both plants and animals. In Arabidopsis, NAE plays an important physiological role in growth/development and response to stress. Although NAEs are reported in tomato, their metabolic pathway remains undiscovered. It is hypothesized that there is a functional FAAH in tomato that hydrolyzes NAEs. To this extent, a putative gene that likely encodes for putative SlFAAH1 protein was identified, cloned, and heterologously expressed. Amidase activity was tested using radiolabeled NAE substrates. Furthermore, expression of putative SlFAAH1 transcripts and protein activity was quantified at different developmental stages to demonstrate endogenous amidase activity in tomato seedlings. In future, molecular and biochemical characterization of tomato FAAH will further test the conserved nature of NAE metabolic pathway in plants.
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Gatbonton-Schwager, Tonibelle N. „Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628.
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