Дисертації з теми "Sphingosine kinases"
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Megidish, Tamar. "Sphingosine as second messenger, sphingosine dependent protein kinases and their substrates /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/9285.
Повний текст джерелаTonelli, Francesca R. "Sphingosine kinases : evaluation of therapeutic potential using prostate cancer cell models." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18199.
Повний текст джерелаBonhoure, Elisabeth. "Rôle de la sphingosine kinase-1 dans la réponse des cellules tumorales à la chimiothérapie." Toulouse 3, 2007. http://www.theses.fr/2007TOU30114.
Повний текст джерелаDayon, Audrey. "Rôle de la sphingosine kinase-1 dans la survie et la progression des cellules tumorales prostatiques LNCaP vers l'androgéno-indépendance." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/307/.
Повний текст джерелаAs prostate cancer cell proliferation is regulated by androgens, strategies aimed at reducing the production of androgens and/or effects are the standard of care in the management of patients with recurrent or advanced disease. Unfortunately all patients become resistant to hormonal manipulation and it is not clear how prostate cancer cells make the transition from being androgen-dependent to being androgen-independent after hormone ablation therapy. We have shown in the Lab that the oncogenic sphingosine kinase (SK) is overexpressed in tumor samples from prostate cancer patients (as compared with normal counterparts). We provide the first evidence that androgen privation induces a differential effect on SK activity in the hormono-sensitive LNCaP prostate cancer cell model. Short-term androgen removal induced a rapid and transient SK inhibition in vitro and in vivo in an orthotopically LNCaP model established in SCID mice. Conversely, long-term removal of androgen resulted in a progressive increase in SK expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SK activity. These results suggest that SK activation upon chronic androgen privation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer
Niaudet, Colin. "Caractérisation et modulation des évènements initiaux contrôlant la mort radioinduite de l'endothélium microvasculaire." Nantes, 2009. https://archive.bu.univ-nantes.fr/pollux/show/show?id=34ca7579-91aa-46a5-bc5a-1291a772a1b6.
Повний текст джерелаHigh dose of ionizing radiation drives microvascular compartment to apoptosis, which controls the whole tissue damaging-process, through the acid sphingomyelinase (ASM)/ceramide pathway. We adressed the connection between ASMase-induced apoptosis and the well-known capacity of ceramide to induce rafts microdomains coalescence into large platforms. Concomitantly to membrane remodeling, irradiation activated p38 death pathway and its blockade partially protected endothelial cells from radiation-induced death. Finally, disorganization of rafts by cholesterol-depletor hindered the p38 activation and the subsequent death-induced microvascular cells. These results suggest a specific membrane controled death mechanism in irradiated endothelial cells, where rafts coalescence leads to p38 activation and apoptosis. We then used sphingosine-1-phosphate (S1P), a ceramide antagonist, to modulate this early wave of radioinduced death in endothelium. We validated the pharmacological use of systemic S1P to restrain acute organ failure in response to severe stress: S1P injection abolished endothelial cells collapse and therefore prevented 15 Gy-induced gastrointestinal syndrome, as well as LPS-induced septic shock, another syndrome driven by microvascular apoptosis. This protection from S1P toward endothelium showed a dual specificity: related sphingolipids failed to offer the same protective effects, and this protection affected only endothelial cells as compared to intestinal epithelial cells or lymphocytes. S1P-induced protective effect is mediated through G-protein coupled receptor then the prosurvival protein Akt, as inhibition of both pathways suppresses the S1P action in vitro and in vivo
Gomez-Brouchet, Anne. "Rôle de la Sphingosine Kinase 1 (SphK1) dans la régulation de la survie des cellules de neuroblastome exposées au peptide Béta-amyloïde." Toulouse 3, 2007. http://www.theses.fr/2007TOU30251.
Повний текст джерелаAlzheimer disease (AD) is a critical problem of public health in the industrialized countries. AD affects 24. 3 million individuals in the world. In France, the number of AD patients represents 5 % of the population over 65 years-old (20 % of people over 85 years-old). Important progress have been made during the last ten years: Mutations were characterized, as well as genetic or environmental risk factors. A better analysis of the two elementary lesions of AD in their distribution and molecular characterization has allowed a better comprehension of the disease. Thus, the description of a dysfunction of proteins APP (Amyloid Precursor Protein) and Tau in sporadic and familial AD has led to therapeutic experiments and tests on cellular or animal models with promising results. Even though the diagnosis of AD still remains related to the neuropathology, it is evoked more precociously due to the progress in neuropsychological evaluation and imaging procedures. The advances in the comprehension of the disease mechanisms should make possible the discovery of new therapeutic targets. .
Thompson, Dawn. "Sphingosine kinase and sphingosine-1 phosphate phosphatase : molecular tools to investigate the role of sphingosine-1-phosphate." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401320.
Повний текст джерелаCongdon, Molly D. "Structure Activity Relationship Studies on Isoform Selective Sphingosine Kinase Inhibitors." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/82129.
Повний текст джерелаPh. D.
Ng, Carl Khee-Yew. "Drought induced guard cell signal transduction involves sphingosine 1 phosphate." Thesis, Lancaster University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250627.
Повний текст джерелаAndrieu, Guillaume. "Rôle de la voie sphingosine kinase/sphingosine 1-phosphate dans le contrôle de la division cellulaire." Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2605/.
Повний текст джерелаCell division is a crucial process for genome maintenance. In cancer, numerous regulators of mitosis are mutated or altered, impeding the quality of chromosome segregation. Tumors exhibit a high chromosomal instability and are frequently aneuploid. These hallmarks promote tumor initiation and progression but are also associated with poor prognosis and therapeutic resistance. The sphingosine kinases/sphingosine 1-phosphate (SphKs/S1P) pathway is a key regulator of several fundamental biological processes including cell proliferation, survival, apoptosis, migration or inflammatory response. Numerous studies have shown that the up-regulation of the SphKs/S1P pathway promotes tumor initiation and progression, invasion, metastasis and resistance to anticancer therapies. We are interested in the role of the SphKs/S1P pathway in cell division regulation. Our data indicate for the first time that SphKs regulate mitotic progression trough S1P production and the interaction with its G protein-coupled receptor S1P5. Furthermore, we showed that the up-regulation of the SphKs/S1P pathway impairs chromosome segregation. Finally, our recent data suggest that the SphKs/S1P pathway may be involved in the acquisition of resistance to mitotic chemotherapeutic agents. Overall, we have identified the SphKs/S1P/S1P5 pathway as a new genuine regulator of mitosis. We give support to the understanding of the implication of the SphKs/S1P pathway in tumoral progression and strengthen its interest as anti-cancer therapeutic targets
Meza, Daniel. "Sphingosine Kinase 1 Inhibitor, A Novel Inducer of Autophagy." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1871.
Повний текст джерелаStillman, Anthony D. "Targeting Sphingosine Kinase 2 as a Treatment for Cholangiocarcinoma." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6067.
Повний текст джерелаLi, Hao. "Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/100741.
Повний текст джерелаDoctor of Philosophy
Cardenas, Alex. "Sphingosine-1-Phosphate in Pancreatic Ductal Adenocarcinoma." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/306974.
Повний текст джерелаStrub, Graham Michael. "INTRACELLULAR TARGETS OF SPHINGOSINE-1-PHOSPHATE." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/5.
Повний текст джерелаMorris, Emily A. "Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/73491.
Повний текст джерелаMaster of Science
Raje, Mithun. "Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors." Diss., Virginia Tech, 2012. http://hdl.handle.net/10919/77051.
Повний текст джерелаPh. D.
Kwong, Eric K. "The Role of Sphingosine Kinase 2 in Alcoholic Liver Disease." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5808.
Повний текст джерелаMachesky, Nicholas John. "The modulation of sphingolipids by human cytomegalovirus and its influence on viral protein accumulation and growth." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1181753517.
Повний текст джерелаChildress, Elizabeth Saunders. "Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/86662.
Повний текст джерелаPh. D.
Sankala, Heidi Milka. "The role of sphingosine kinase 2 in cell growth and apoptosis /." Also available to VCU users online at:, 2007. http://hdl.handle.net/10156/1902.
Повний текст джерелаLim, Keng Gat. "Discovery and characterisation of novel anticancer compounds acting on sphingosine kinase." Thesis, University of Strathclyde, 2011. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=23882.
Повний текст джерелаSankala, Heidi M. "The Role of Sphingosine Kinase 2 in Cell Growth and Apoptosis." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd/1242.
Повний текст джерелаSauer, Lysann. "Cross-regulation of prosaposin and sphingosine kinase signalling in prostate cancer." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9555.
Повний текст джерелаGillies, Laura. "The sphingosine 1 phosphate receptor 5 and sphingosine kinase 1 and 2 are localized in centrosomes : role in regulating cell division." Thesis, University of Strathclyde, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501800.
Повний текст джерелаCamaré, Caroline. "Rôle de la voie sphingomyelinase neutre de type 2 - sphingosine kinase 1 - sphingosine-1-phosphate dans l'effet angiogénique des LDL oxydées." Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2648/.
Повний текст джерелаAtherosclerosis and relative complications represent the main cause of morbi-mortality in western countries and arise a major problem for public health. Many risk factors have been described, in particular hypercholesterolemia linked to circulating LDL. The oxidation of LDL constitutes a decisive stage in atherogenesis. The vascular wall of the medium and large arteries is vascularized by a microcapilaries plexus (vasa vasorum) located in adventice, and in charge to bring oxygen and nutrients to the most external layers of the arterial wall. Although, no capillaries are found in the intima or media of normal arteries, we observe neovascularization under intimal hyperplasia of atherosclerotic arteries. As oxidized LDL could display angiogenic properties, they may contribute to this neovascularization, taking part in plaque growth but also in increasing risk of intraplaque heamorrage and destabilization leading to atherothrombotic complications. The angiogenic mechanisms of oxidized LDL is yet incompletely known, and the involvement of sphingosine-1-phosphate (S1P), a second messenger of sphingolipid pathway, well known for its angiogenic properties, has never been reported in oxLDL-induced angiogenesis. The aim of this work is to evaluate the involvement of sphingolipid pathway and its mechanisms of activation, with subsequent generation of S1P, in proangiogenic effects of oxidized LDL on microvascular endothelial cells. In a first part, we have demonstrated a biphasic effect exhibited by oxidized LDL in HMEC-1 (Human Microvascular Endothelial Cells), low oxLDL concentrations (20 to 50µg/ml) being angiogenic, whereas higher concentrations being not toxic yet (100µg/ml) are non angiogenic. Beyond these concentrations, as expected, a toxic effect was observed. Inhibition of SK1 (sphingosine kinase-1) expression by using a specific SiRNA, and use of S1P blocking antibody (Sphingomab(tm)), exibit an efficient inhibition of oxLDL-induced tubulogenesis of endothelial cells in vitro. Angiogenesis in C57/Bl6 mice (using Matrigel plug assay containing oxLDL), is efficiently prevented by administration of the S1P blocking antibody Sphingomab(tm), defining the major role of this bioactive lipid in the oxLDL angiogenic signal, in vitro and in vivo. Mechanisticaly speaking, ox-LDL-induced SK1 activation and angiogenesis are blocked by using anti-CD36 and anti-LOX-1 blocking antibody, showing the involvement of oxLDL scavenger receptors in this signaling. The use of a sphingosine kinase inhibitor of VEGFR2 blocks ox-LDL-induced angiogenesis in the same range as exogenous S1P-induced angiogenesis, evoking a cross-talk between VEGFR and membranary S1P receptors, in the absence of ox-LDL-induced VEGF synthesis in HMEC-1. In a second part, we have shown that ox-LDL-induced SK1 activation and subsequent S1P synthesis, was tightly linked to the amoung nSMase2 activation in endothelial cells in vitro, involving also oxidative stress and p38MPAK. The use of a chemical inhibitor of nSMase2 efficiently blocks both ox-LDL-induced angiogenesis and SK1 activation in vitro. The time course of ROS generation and p38MAPK phosphorylation in HMEC-1 submitted to angiogenic doses of oxLDL appears earlier than enzymes activation of sphingolipid pathway. Using antioxydants as NAC and trolox, as well as a phospho-p38MPAK inhibitor, we block both angiogenesis and nSMase2 and SK1 activation in vitro, evoking implication of oxidative stress and p38MPAK in this signalling amoung of sphingolipid pathway. In a third part, we have studied the link between oxLDL induction of sphingolipid pathway and connexine-43, a constitutive protein of gap junctions allowing signal transduction between adjacent cells. Through the use of two connexine pharmacological inhibitors, we have obtained an efficient inhibition of oxLDL-induced SK1 activation and tubulogenesis in vitro, evoking that gap junctions may take part in oxLDL angiogenic signalling, implicating S1P generation. In the perspective of this work, we plan to intensify the knowlegde of mechanisms involving connexine-43 in this signaling, particularly in relation to sphingolipid pathway and p38MAPK. Thereafter we would like to establish a link between this work and the developement of plaque neovascularization in vivo, in support of SK1 or connexines-43 staining on endarterectomy samples of human carotids from patients. These results arise new targets (S1P, connexine-43) implicated in development of intraplaque neoangiogenesis, and new therapeutic possibilities to limit atherothrombotic complications that significantly worsen the prognosis of atherosclerotic patients
Gstalder, Cécile. "Rôle de la voie sphingosine kinase 1/sphingosine 1-phosphate dans l'adaptation à l'hypoxie intratumorale des adénocarcinomes rénaux à cellules claires." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30095/document.
Повний текст джерелаClear cell renal cell carcinomas (ccRCC) represent 70% of renal tumors. Because of their dense and irregular vascular network, ccRCC become hypoxic and therefore resistant to chemotherapies. Hypoxia promotes tumor aggressiveness via the activation of HIF-1alpha and HIF-2alpha (Hypoxia-Inducible Factors). For this reason, the control of intratumoral hypoxia and HIF in ccRCC could be a relevant therapeutic strategy to improve the efficacy of current treatments. In this study, we show for the first time that the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway regulates HIF-2alpha in vitro and in vivo. Our results indicate that SphK1 regulates HIF-2alpha intracellular level and transcriptional activity in ccRCC cell lines that are representative of some clinical ccRCC subgroups. Our data also involve extracellular S1P, via its receptor S1P1, in the regulation of HIF-1alpha and HIF-2alpha. In addition, in a ccRCC mouse model, we show that FTY720 - an inhibitor of the SphK1/S1P pathway- transiently decreases HIF-1alpha and HIF-2alpha intratumoral level. This is associated with a transient remodeling of the tumor vascular network indicating that FTY720 induces a vascular normalization that leads to transient tumor oxygenation. Finally, we show that this treatment sensitizes a ccRCC mouse model to chemotherapy. Overall, these results validate the key role of the SphK1/S1P pathway in the adaptation to hypoxia in ccRCC cell and animal models. Our results provide a mechanistic basis to target the SphK1/S1P pathway with FTY720 by increasing the efficacy of chemotherapy in ccRCC. They are a prerequisite for clinical transposition as FTY720 is a drug approved used in human clinic
Bouquerel, Pierre. "Rôle de la sphingosine kinase 1 dans la régulation de l'hypoxie intratumorale." Toulouse 3, 2012. http://thesesups.ups-tlse.fr/2174/.
Повний текст джерелаHypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, increased tumor growth and resistance to treatments. The activation of the transcription factor hypoxia-inducible factor 1 (HIF-1) has been identified as the master mechanism of adaptation to hypoxia. Whereas initial characterization of hypoxia-induced transcription emphasized on HIF-1, there is now evidence that HIF-2, which is closely related to HIF-1, could regulate unique genes and physiological functions. Notably, HIF-2, rather than HIF-1, has been shown to play a critical role in clear cell renal carcinoma (ccRCC). We have previously identified the sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway - which elicits various cellular processes including cell proliferation, cell survival or angiogenesis - as a new modulator of HIF-1 activity. Considering the crucial role of HIF-2 in ccRCC, it was essential to understand the role of the SphK1 signaling in these tumors. To this end, the mechanisms underlying the regulation of HIF-2a level and activity, via the SphK1 signaling, have been investigated. These in vitro studies have been conducted in various ccRCC models exhibiting different HIF-1a and HIF-2a status, and representing all the sub-groups found in human clinic (which can produce either HIF-1a and HIF-2a or HIF-2a alone). Our data indicate that SphK1 regulates HIF-2a level in several cancer cell models including ccRCC. Depletion of SphK1 decreased HIF-2a level and consequently resulted in decreased expression levels of HIF-2a responsive genes. In ccRCC, SphK1 stimulates translation of HIF-2a via p70-S6kinase and mTOR pathway. Upstream, we have established that Phospholipase D (PLD) is responsible for the up-regulation of SphK1, and that inhibition of PLD leads to a decrease in SphK1 activity and in HIF-2a level and activity. Moreover inhibition of reactive oxygen species (ROS) production abolished PLD/SphK1/ HIF-2a pathway. Overall, we have identified a new molecular mecanism whereby a ROS/ PLD/SphK1 signaling pathway regulates HIF-2a. We provide evidence that SphK1 act as a master regulator for HIF-2a and giving support to its inhibition as a valid strategy for ccRCC and others cancers for which HIF-2a is particularly relevant (lung, neuroblastoma)
Farinha, Garcao Nunes Joao Pedro. "Investigating the role of Sphingosine Kinase 1 pathway in cancer cell-monocyte interactions." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29864.
Повний текст джерелаGasser, Amanda Lynn. "Characterization of Influenza:Streptococcus pneumoniae synergistic disease and potential for disease alleviation via sphingolipid therapy." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/51569.
Повний текст джерелаMaster of Science
Guinan, Jack Henry. "Sphingosine-1-Phosphate and Stromal Cells Contribute to an Aggressive Phenotype of Ovarian Cancer." Thesis, Virginia Tech, 2017. http://hdl.handle.net/10919/86438.
Повний текст джерелаMaster of Science
Bats, Marie-lise. "Bases cellulaires et moléculaires du rôle de la Sphingosine 1-phosphate dans la progression et la résistance du mélanome cutané." Toulouse 3, 2014. http://www.theses.fr/2014TOU30034.
Повний текст джерелаMetastatic melanoma is considered to be one of the most aggressive and treatment-resistant human cancer. Despite advances in the understanding of tumor biology and genetics of melanoma, until recently systemic therapy was ineffective against this invasive cancer. Many evidences support the notion that the adjacent microenvironment plays a key role in the progression of this tumor. Defining the molecular signals that control the bidirectional dialogue between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. The first part of our work aimed at defining the role of sphingosine-1-phosphate (S1P), a bioactive sphingolipid that promotes tumor cell migration and survival, in melanoma-stroma interactions. Transcriptomic analysis of human melanoma cell lines showed an increased expression of sphingosine kinase-1 (SK1), the enzyme that produces S1P, as compared to normal melanocytes. Such an increase was also observed by immunohistochemistry in melanoma specimens as compared to nevi, and occurred downstream of ERK activation due to BRAF or NRAS mutations. Importantly, migration of melanoma cells was not affected by changes in SK1 in tumor cells but was stimulated by comparable modifications of S1P-metabolizing enzymes in co-cultured dermal fibroblasts. Reciprocally, incubation of fibroblasts with the conditioned medium from SK1-expressing melanoma cells resulted in their differentiation to myofibroblasts, increased production of matrix metalloproteinases, and enhanced SK1 expression and activity. In vivo tumorigenesis experiments showed that the lack of S1P in the microenvironment prevented the development of orthotopically injected melanoma cells. Finally, local tumor growth and dissemination were enhanced more efficiently by co-injection of wild-type skin fibroblasts than by fibroblasts from Sphk1-/- mice. Altogether, our findings demonstrate that SK1/S1P can modulate the communication between melanoma cells and dermal fibroblasts, pointing out the relevance of SK1 as a potential therapeutic target in melanoma progression. Moreover, we previously reported that S1P Lyase expression, the enzyme responsible for irreversible degradation of S1P, was down-regulated in human skin melanoma cells as compared to normal melanocytes. The second part of our work aimed at defining the effect of S1P Lyase on the response of melanoma cells to antitumor therapies. Here we showed that disruption of S1P Lyase by siRNA enhanced resistance of A375 melanoma cells to Dacarbazine (DTIC), the common chemotherapy used to treat advanced melanoma. In contrast, we reported increased apoptosis in melanoma cells expressing S1P Lyase, as a consequence of increased expression of pro-apoptotic and decreased anti-apoptotic members of the Bcl-2 family. Moreover, S1P Lyase-induced cell death was enhanced in tumor cells treated by the Bcl-2 antagonist ABT-737 suggesting that S1P Lyase could act as a new regulator of Bcl-2-mediated cell survival in melanoma. Interestingly, S1P Lyase overexpression was also associated with an increased expression of p53 as a consequence of the downregulation of its key regulator Mdm4. Furthermore, A375 cells overexpressing S1P Lyase exhibited a decreased expression of Microphthalmia-associated transcription factor (MITF), one of the master regulators of melanogenesis and melanoma progression, also known to up-regulate Bcl-2 transcription. Finally, S1P Lyase promoted PTEN activation by decreasing its phosphorylation. By controlling the expression of key proteins in the regulation of apoptotic pathways, SPL could be a new target to improve the efficacy of anti-melanoma therapies
Serrano, Sanchez Martin. "Rôle de l'axe Sphingosine Kinase 1 / Sphingosine -1- Phosphate dans la régulation de l'expression de la Cyclooxygénase 2 dans le myomètre de rate gestante." Paris 11, 2009. http://www.theses.fr/2009PA11T075.
Повний текст джерелаPrice, Megan. "Sphingosine-1-phosphate in mast cell-mediated allergic responses." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/254.
Повний текст джерелаCorro, Morón Macarena. "Novel Strategies for the Syntheses of Sphingosine Kinase Inhibitors, b-Fluoroamines and Enantioenriched Allenes." Doctoral thesis, Universitat Rovira i Virgili, 2018. http://hdl.handle.net/10803/665123.
Повний текст джерелаLos esfingolípidos tienen un papel muy importante tanto en procesos biológicos como fisiológicos y se convierten los unos en los otros por la acción de enzimas. El futuro celular está determinado por el balance que controla la síntesis de ceramida, esfingosina y esfingosina-1-fosfato, esfingolípidos asociados al cáncer. Mientras que tanto la ceramida como la esfongosina están asociadas a procesos de apoptosis celular, la esfingosina-1-fosfato está vinculada a la proliferación. Debido a esto, muchos grupos de investigación están centrando sus trabajos en la síntesis de inhibidores de esfingosina quinasa, enzima que promueve la formación de la esfingosina-1-fosfato. En el capítulo 3 se describe la síntesis de una nueva familia de inhibidores de esfingosina quinasa y se muestran los valores de inhibición encontrados para cada compuesto. Además, también se han realizado estudios de docking para tratar de predecir las posibles interacciones de nuestros compuestos con la enzima. En el capítulo 4 se desarrolla una nueva metodología para obtener β-fluoroaminas desde carbamatos como materiales de partida. Suponemos que la reacción procede via aziridina y apertura de la misma aunque nos encontramos con diastereoselectividad opuesta a la esperada. A pesar de que se han realizado varias pruebas para tratar de confirmar los mecanismos propuestos, estos no nos han ayudado a elucidar ninguno y, por tanto, se deben seguir haciendo pruebas antes de poder confirmar algo. En el capítulo 5 se describe la síntesis enantioselectiva de alenos mediada por cobre. Durante el estudio se observó que la enantioselectividad era favorecida con la presencia de fosfitas y que el uso de unas fosfitas voluminosas conducía a una enantioselectividad opuesta. Además, se comprobó que este tipo de reacción está influenciada por las características estéricas y electrónicas de los sustratos y que había una tolerancia moderada hacia distintos grupos funcionales.
Sphingolipids play a central role in numerous biological and physiological processes and they are converted into each other through the action of enzymes. Ceramide, sphingosine and sphingosine-1-phosphate have been found to be involved in cancer processes and the balance that controls their syntheses determines the cell fate. Whereas ceramide and sphingosine are associated with apoptosis, sphingosine-1-phosphate is related to cell proliferation. In this context, many research groups are investigating the synthesis of inhibitors for sphingosine kinase, enzyme which promotes the synthesis of sphingosine-1-phosphate. In chapter 3, we describe the synthesis of new sphingosine kinase inhibitors and also show the inhibitory potency of all of them. Besides, docking studies to predict interaction between our compounds and the enzyme are also presented. In Chapter 4, we develop a new strategy in the synthesis of β-fluoroamines starting from carbamates. Presumably, the reaction proceeds via aziridination and ring-opening processes in which we have found an unexpected diastereoselectivity. Fluoroamines present syn configuration instead trans expected. Although several tests have been performed to explain the observed selectivity, further studies should be done before confirming or discarding the suggested mechanisms. In Chapter 5, we work in a novel enantioselective synthesis of allenes mediated by copper. It was found that enantioselectivity could be increased by the presence of phosphites to give anti-elimination. The use of bulkier phosphites led to syn-elimination. This process is influenced by steric and electronic properties of substrates and present moderate tolerance towards different groups.
Castelain, Lauriane. "Sphingosine kinase 1, transition épithélio-mésenchymateuse et résistance primaire aux inhibiteurs pharmacologiques de l'EGFR." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066595.
Повний текст джерелаEpithelial-mesenchymal transition (EMT) and sphingosine kinase 1 (SPHK1) high expression are often seen in cancers. Our study of genomic and gene expression data in pulmonary adenocarcinomas (AP) shows that SPHK1 high expression correlates with both gains in the region encompassing the SPHK1 locus, and an EMT gene expression signature in invasive tumors. SPHK1 expression is restricted to tumors cells. SPHK1 overexpression in AP cells, as well as exposure to its productsphingosine-1-phosphate (S1P),induce an EMT -in a reversible manner for S1P. SPHK1 overexpression also activates NF-kB. Overexpression of FLIP – an antiapoptotic factor - activates NF-kB, induces an EMT, and increases SPHK1 expression, suggesting an amplification loop between NF-kB and SPHK1. EMT and FLIP overexpression are known to favor primary resistance to EGFR pharmacological inhibitors (EGFR TKI). We show that SPHK1 overexpression in A549 cells slightly decreases cell sensitivity to gefitinib, while pharmacologic inhibition of SPHK1 or serum S1P depletionincrease it. Downregulation of SPHK1 expression induces apoptosis of A549 cells even when FLIP is overexpressed. Activation and maintenance of EMT are generally attributed to contextual signals from the stroma. Here, we show that tumor cells themselves favor SPHK1 overexpression, which can led to EMT in cell-autonomous manner. In addition, FLIP overexpression which is implicated in EGFR TKI resistance, cannot prevent apoptosis that is induced by SPHK1 invalidation
Wang, Yu. "Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion." Kyoto University, 2017. http://hdl.handle.net/2433/226770.
Повний текст джерелаLiu, Yanyan. "Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion." Kyoto University, 2019. http://hdl.handle.net/2433/243293.
Повний текст джерелаChen, Yiqun. "Roles of sphingosine kinase in aging and longevity in Caenorhabditis elegans and in neurodegeneration in mice." Thesis, Lyon, École normale supérieure, 2013. http://www.theses.fr/2013ENSL0815.
Повний текст джерелаAdvances in medical technology and hygiene standards have increased human life expectancy at unprecedented rates worldwide. Nevertheless, one of the consequences of a growing elderly population is an increased prevalence of age-related disease. A scientific understanding of the underlying biological mechanisms of aging is essential to develop effective treatments for age-related diseases and to provide adequate health care to the elderly. In this study, we investigated part of the genetic network that mediates lifespan extension resulting from dietary restriction. We focused on the contribution of a conserved gene encoding the enzyme sphingosine kinase, and describe for the first time its role in diet-mediated longevity.This thesis is composed of two parts. In the first part, we used the nematode Caenorhabditis elegans as a model organism to investigate the role of the sphingosine kinase gene (sphk-1) in aging. We found that worms carrying a sphk-1 null mutation (sphk-1(ok1097)) are long-lived and do not benefit from further lifespan extension upon dietary restriction (DR), a regimen that extends the lives of wild-type worms. sphk-1(ok1097) animals exhibit many phenotypes displayed by animals subjected to DR, suggesting that sphk-1(ok1097) acts through the DR longevity pathway. In support of this, sphk-1(ok1097)-mediated lifespan extension requires the essential DR regulator, SKN-1b, and, similar to SKN-1b, sphk-1 is expressed in head neurons. A search for possible sphk-1(ok1097)-associated longevity determinants suggested the involvement of the TOR/autophagy pathway. Moreover, we found that mutations in ceramide pathway genes other than sphk-1 have similar effects on longevity. Finally, we discovered that sphk-1 mutants fail to reduce germ cell numbers in response to DR. Because such a reduction appears to be an essential feature of DR-mediated lifespan extension, we propose that this failure to reduce germ cell numbers may explain why sphk-1(ok1097) mutant longevity is not extended when nutrient levels are low.The second part of this study investigated the role of sphingosine kinase in brain function during normal and pathologic aging. We examined the expression of sphingosine kinase genes in wild-type mice and in a mouse model of Alzheimer’s disease (AD)-like neurodegeneration. Expression of both mouse SphK genes was increased in the brains of AD-like mice as early as 6 months of age. Chronic administration of an SphK inhibitor elevated the brain weight of AD-like mice and improved their performance in the beam walking test, but not in hippocampus-dependent memory tasks. Treatment of wild-type mice with SKI-II had little effect, but calorie restriction reduced the expression of SphK mRNA in the brain, suggesting that sphingosine kinase may play some conserved roles in nutrient sensing pathways
在工业化水平越来越高的当今社会,人口的老龄化正逐渐成为一个严重的社会问题。医疗手段的发展、生活水平的提高使得人们的寿命在不断增加,而与此同时生育率并没有同步增加,这就导致老年人口在整个社会人口中的比重快速增长,因此,衰老以及一些相关的疾病就得到了人们越来越多的关注,也正在成为一个越来越热门的科研领域。从科研工作者的角度,我们希望能够通过实验手段破解衰老及其相关疾病的机制从而寻找延缓衰老或治疗相关疾病的方法。在本论文中,我们研究了一个通过限制饮食来调控寿命的基因网络的一部分。我们的主要研究对象是编码鞘氨醇激酶的基因(SphK),我们第一次发现了它在饮食介导的寿命调控中的作用。本论文由两个章节组成。在第一章中,我们使用秀丽隐杆线虫作为模式动物来研究鞘氨醇激酶基因(sphk-1)在其衰老调控过程中的作用。在研究中,我们发现,携带一种sphk-1 删除突变(sphk-1(ok1097))的突变体线虫的平均寿命显著延长,而饮食限制(DR)并不能进一步延长它的寿命。另外,这种突变体还表现出一系列与受饮食限制调控的动物相类似的表型,尽管并不是全部。这些结果都表明sphk-1 基因通过饮食介导的途径参与线虫的寿命调控。我们随后的研究显示,由sphk-1 突变引起的寿命延长依赖于DR 的一个调控因子:SKN-1b;并且,与skn-1b 类似,sphk-1 表达的位置也在线虫头部的神经元。对于其它DR 相关因子的研究还发现线虫sphk-1(ok1097)突变引起的寿命延长可能与TOR 及自噬通路的作用有关。此外,我们还发现,不仅是sphk-1,神经酰胺通路中的其它基因对于寿命调控也有类似的效果。最后,我们的研究结果显示,DR 未能减少sphk-1(ok1097)突变体线虫的生殖细胞数量,这一发现或许能够解释为什么DR不能够进一步延长sphk-1(ok1097)突变体线虫的寿命。在第二章中,我们使用了一种模拟阿尔茨海默症(AD)的小鼠模型来测试哺乳类SphK 基因在神经退行性病变中的作用。我们发现,在模型小鼠脑组织中,两种哺乳类SphK 基因的表达水平与它们的同窝对照相比显著增加,而这一显著差异早在6 月龄的小鼠脑中就能发现。在后续的实验中,我们给这些小鼠喂食了一种SphK 的抑制剂——SKI-II。这种抑制剂显著改善了模型小鼠在平衡木实验中的表现,并且显著增加了它们的脑重量,但对于海马依赖性的记忆并没有改善。在另一个实验中,给野生型小鼠注射SKI-II 并没有表现出明显的差异,但热量限制(CR)降低了野生小鼠脑中两种SphK基因的表达量,这一与线虫中类似的结果提示,鞘氨醇激酶在营养通路中可能有一些进化保守的功能。
Martin, Claire. "Rôle de la signalisation sphingosine kinase-1 sphingosine 1-phosphate dans les interactions stroma-cellules épithéliales au sein des métastases osseuses du cancer de la prostate." Toulouse 3, 2009. http://thesesups.ups-tlse.fr/513/.
Повний текст джерелаProstate cancer (PCa) has a high predisposition to metastasize to bone. PCa bone metastases are associated with increased osteoblastic activity. We studied the role of the sphingolipid signalisation in the interactions between osteoblasts (OB) and PCa cells. The sphingolipid metabolite sphingosine 1-phosphate (S1P), produced by the oncogenic lipid kinase sphingosine kinase-1 (SphK1) - is a lipid mediator playing a major regulatory role in tumor cell growth and survival. We studied the role of SphK1 in androgen induced osteoblast proliferation. We provide the first evidence that SphK1 is instrumental in mediating androgen-induced OB proliferation. Androgen triggered OB cell growth, which was associated with a rapid stimulation of SphK1 and activation of both AKT and ERK signalling pathways. We also investigated the potential role of S1P, as a paracrine factor implicated OB-PCa cells cross talk. Our goal was to investigate the potential role of S1P, as a putative bone-derived factor that could stimulate growth or survival of PCa cells. We have found that osteoblastic cells exhibit a very high SphK1 activity, which could render OB extremely resistant to chemotherapeutics such as taxanes. Conditioned medium from OB did protect the PCa cells from the killing effects of taxanes. The cytoprotective effect of OB-derived conditioned medium on PCa cells was abolished when SphK1 activity was first inhibited in OB. These results suggest that SphK1/S1P pathway play an important role in OB response to androgen present in the microenvironment and could contribute to PCa bone metastasis progression
Garandeau, David. "Rôle du métabolisme de la sphingosine 1-phosphate dans la résistance thérapeutique des cellules de mélanome aux inhibiteurs de BRAF." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30134.
Повний текст джерелаThe treatment of metastatic melanoma has changed considerably in recent years with the development of targeted therapies, which have shown a significant benefit in overall survival. In particular, the inhibition of the frequently mutated serine-threonine kinase BRAF, by Vemurafenib (PLX4032) showed that survival rates increase by 6 to 8 months compared to standard chemotherapy, Dacarbazine. However, a very small proportion of patients will respond to the long term, and the majority of patients relapses in a median of 6 months. Cellular mechanisms have been identified in the appearance of this acquired resistance, including the involvement of MITF, a major transcription factor of melanocytes, as well as changes in the expression of several members of Bcl-2 family. However, a better understanding of these mechanisms seems essential, as is the use of new therapeutic strategies to optimize treatment efficacy and duration of clinical benefit. Our group recently showed some alterations of ceramide metabolism and its derivative sphingosine 1-phosphate (S1P) in human melanoma cells compared to healthy melanocytes. For instance, S1P lyase (SPL), which degrades S1P, is under-expressed. Conversely, sphingosine kinase 1 (SK1), which produces S1P, is over-expressed in tumor cells, as a direct result of BRAF mutation. These alterations increases the levels of S1P. This lysophospholipid promotes cell survival and the resistance to therapeutic agents in a variety of tumor cells. This PhD project aimed at defining whether S1P metabolism could modulate the resistance of human melanoma cells to PLX4032. Here, we show that SPL overexpression or pharmacological inhibition of SK1 by SKI-I sensitizes metastatic melanoma cells to PLX4032-induced apoptosis. This phenomenon is associated with a decreased expression of the master regulator of melanocyte differentiation MITF as well as its direct cellular target Bcl-2. The decrease in MITF protein can be reversed by treating cells with exogenous S1P. Interestingly, we also report for the first time an increased expression of SK1 as well as the S1P receptors, S1PR1 and S1PR3, in melanoma cells with acquired resistance to PLX4032 as compared to sensitive counterparts. These modifications are associated with high expression of MITF. Overexpression of SPL, treatment with SKI-I or antagonists of S1PR1 ans S1PR3, strongly overcomes acquired resistance to PLX4032 through a decrease in the expression of S1PR, MITF as well as Bcl-2. Thus, by controlling the expression of key proteins in melanoma cell survival and resistance, S1P metabolism could represent a new therapeutic approach to enhance the effectiveness of targeted therapies
Tawati, Salha M. "Design, synthesis and biological evaluation of sphingosine kinase inhibitors for the treatment of prostate cancer." Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30298.
Повний текст джерелаZhang, Xiwen. "KNOCKOUT OF SPHINGOSINE KINASE 1 ATTENUATES RENAL INTERSTITIAL FIBROSIS IN UNILATERAL URETERAL OBSTRUCTION (UUO) MODEL." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5010.
Повний текст джерелаRodgers, Alayna. "Regulation of p42/p44 mitogen activated protein kinase by sphingosine-1-phosphate in embryonic stem cells." Thesis, University of Strathclyde, 2009. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=12413.
Повний текст джерелаImbert, Caroline. "Rôle de la sphingosine kinase-1 dans la réponse immunitaire anti-tumorale et dans le traitement du mélanome par immunothérapie." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30192.
Повний текст джерелаThe emergence of new therapeutic approaches, thanks to immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD-1, have revolutionized the management of melanoma. However, the objective response rates to these treatments remain relatively low and severe adverse events or resistance can occur. This is why it is essential to understand the mechanisms that underlie resistance and identify predictive biomarkers of the response to ICI in order to adapt the therapeutic strategy. Our group identified perturbations of sphingosine 1-phosphate (S1P) metabolism in melanoma cells. In particular, the overexpression of sphingosine kinase (SK1), an S1P-producing enzyme that promotes tumor progression by stimulating stromagenesis, angiogenesis and polarization of macrophages toward M2 Phenotype. Interestingly, S1P is a well-known regulator of the activation, differentiation and trafficking of many immune cells. This thesis aims at determining whether the inhibition of SK1 improves the anti-tumor immune response as well as the efficacy of ICI. We found that an increased expression of SK1 in tumor cells is significantly associated with shorter survival in patients with metastatic melanoma treated with anti-PD-1. In a mouse model, we also demonstrated that a decreased SK1 expression in tumors leads to reduction of melanoma growth as well as expression of several immunosuppressive factors in the TME. These modifications are associated to significant reduction of proliferation, infiltration of regulatory T cells (Treg) and consequently to an increase in the CD8+/Treg ratio, which is associated with good prognosis. A SK1-dependent immunosuppressive signature has also been observed in human melanoma biopsies. Importantly, our data reveal that inhibition of SK1 strongly enhances the efficacy of ICI, such as anti-CTLA-4 or anti-PD-1, leading to tumor rejection and improved survival in a mouse model of melanoma. Significant results have also been obtained in breast and colon cancer models. Overall, we show that: i) SK1 targeting in melanomas leads to an increase of the intratumoral CD8 + / Treg ratio, ii) the combination of SK1 inhibition with ICI greatly enhances mice survival, iii) SK1 could be a new predictive biomarker of response to ICI in humans. Altogether, our data identified SK1 as a new checkpoint lipid kinase that could be targeted to improve response to ICI in several cancers
Swensen, Adam Clayton. "Investigation of Dynamic Biological Systems Using Direct Injection and Liquid Chromatography Mass Spectrometry." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6574.
Повний текст джерелаLe, Scolan Erwan Pierre Laurent. "Recherche d'altérations génétiques impliquées dans la transformation des proérythroblastes transgéniques pour spi-1 : dérégulation transcriptionnelle du gène codant pour la sphingosine kinase de type 1." Paris 7, 2005. http://www.theses.fr/2005PA077035.
Повний текст джерелаBabahosseini, Hesam. "Nanoparticle-Based Drug Delivery and the Impacts on Cancer Cell Biophysical Markers." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/79689.
Повний текст джерелаMaster of Science
Drosos, Zacharias [Verfasser], Lars [Akademischer Betreuer] Hanker, and Markus [Akademischer Betreuer] Meier. "Die prognostische Bedeutung der Expression von Acid-Ceramidase (ASAH1) und Sphingosin-Kinase 1 (SPHK1) bei Patientinnen mit Ovarialkarzinom / Zacharias Drosos ; Akademische Betreuer: Lars Hanker, Markus Meier." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2021. http://d-nb.info/1236386272/34.
Повний текст джерелаBöhm, Andreas [Verfasser], Bernhard [Akademischer Betreuer] Rauch, and Joachim [Akademischer Betreuer] Ernst. "Regulation der Sphingosin-Kinase 1 (SPHK1) durch den aktivierten Gerinnungsfaktor X (FXa) und den Protease-aktivierten Rezeptor 2 (PAR-2) in glatten Gefäßmuskelzellen / Andreas Böhm. Gutachter: Bernhard Rauch ; Joachim Ernst." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2013. http://d-nb.info/1043802142/34.
Повний текст джерела