Dissertations / Theses on the topic 'Mechanotransduction'
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Huang, Wei. "Polycystin-1 and Bone Mechanotransduction." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10279.
Full textChronopoulos, Antonios. "Mechanotransduction in health and disease." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/56622.
Full textPucker, Andrew David. "Mechanotransduction in the Ciliary Muscle." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460647729.
Full textMalone, Amanda Michelle Dolphin. "Mechanotransduction mechanisms in bone cells /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
Full textKuck, Jan L. "Mechanotransduction in red blood cells." Thesis, Griffith University, 2023. http://hdl.handle.net/10072/421118.
Full textThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Sci & Soc Wrk
Griffith Health
Full Text
Bays, Jennifer McQuown. "Mechanisms of E-cadherin mechanotransduction." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5711.
Full textBouclet, Adrien. "Evolutionary implication of mechanotransduction in development." Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-01071238.
Full textAragona, Mariaceleste. "Role of YAP/TAZ in Mechanotransduction." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422159.
Full textLe cellule percepiscono il loro microambiente non solo attraverso molecole segnale e fattori solubili ma anche attraverso stimoli fisici e meccanici. Le cellule traducono questi stimoli in segnali biochimici attraverso un processo definito meccanotrasduzione, in grado di regolare numerosi aspetti del comportamento cellulare, tra cui crescita, differenziamento e progressione tumorale. Tuttavia, non è ancora noto come la percezione dei segnali meccanici si traduca nell’attivazione di specifici fattori di trascrizione a livello nucleare. Questo lavoro individua YAP (Yes-associated protein), e TAZ (transcriptional coactivator with PDZ-binding motif, anche noto come WWTR1), omologhi di Yorkie in Drosophila, quali fattori di trascrizione in grado di rispondere ai segnali meccanici generati dalla rigidità della matrice extracellulare e dalla forma propria di ogni singola cellula. Questa regolazione richiede l’attivazione della GTPase Rho e la presenza di un citoscheletro di actina contrattile, ma è indipendente dall’attività della via di segnale delle chinasi Hippo e LATS. Non solo YAP/TAZ vengono regolati da segnali meccanici, ma sono anche funzionalmente richiesti per il differenziamento delle cellule staminali mesenchimali indotto dalla stiffness (elasticità o rigidità) della matrice e per la sopravvivenza delle cellule endoteliali regolata dalla geometria cellulare. In maniera complementare, l’espressione di una forma attivata di YAP domina sull’azione degli stimoli fisici nel determinare il destino cellulare. Queste scoperte identificano YAP/TAZ come sensori e mediatori degli stimoli meccanici indotti dal microambinete cellulare.
Dutour, Provenzano Gaëlle. "Role of intermediate filaments in mechanotransduction." Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS364.
Full textCells continuously adapt to their microenvironment. In particular, they modulate their morphology, growth, division, and motility according to the biochemical and physical properties of the extracellular matrix (ECM). Cells are equipped with adhesive structures called FAs, allowing them to interact with ECM proteins through the core transmembrane proteins called integrins and to sense the nature and the rigidity of the ECM. This information are transduced by FA proteins and lead, for instance, to changes in acto-myosin-mediated mechanical tension. Downstream signalling pathways also reach the nucleus; gene expression is then modified and may, in return, affect the composition of FAs or of the ECM proteins for adaptative cell response. Here, we hypothesized that, in addition to signalling pathways, a direct mechanical coupling between the events occurring at the cell periphery and the nucleus may participate in the transmission of mechanical cues and the regulation of nuclear functions. Although intermediate filaments (IFs) have extremely interesting mechanical properties and resist high tension load, their involvement in mechanotransduction pathways remains elusive. Using astrocyte as a model, due to its specific combination of IFs: vimentin, GFAP, nestin, and synemin, we studied first the effect of substrate rigidity on the nucleus morphology and function, and on the organisation of IFs around the nucleus. Then, we investigated the role of IFs in rigidity-induced nuclear changes. Using a combination of microfabrication techniques, biochemical and microscopy methods, we showed that substrate rigidity affects the nucleus shape, volume, and structure of the chromatin and the recruitment of transcription factor (YAP) and IFs are mediating these changes. Our results suggest that IFs form a cage-like structure around the nucleus in a rigidity-dependent manner: stiffer substrates promote the formation of a cage of vimentin and nestin. In the absence of IFs, the nuclear changes induced by rigidity are different than with IF. The nucleus increases its size in soft substrate, together with an increase in tension measured by YAP localising in the nucleus. The structure of the chromatin is changed. Altogether, the results obtained during our investigation give a better understanding of the role of intermediate filaments in the mechanosensitive nuclear responses
Huesa, Carmen. "Mechanotransduction in cells of the osteoblast lineage." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25468.
Full textPardo, Pastor Carlos 1989. "Piezo ion channels in cancer cell mechanotransduction." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664209.
Full textLa dependència mecànica de la transformació i la metàstasi és un camp d’estudi / de recerca emergent, però el paper que hi juguen els canals iònics mecanosensibles s’ha omès fins ara. Aquesta tesi se centra en els rols dels canals Piezo1 i Piezo2 en la transducció d’estímuls mecànics per cèl·lules canceroses, com ara confinament, adhesió, rigidesa del substrat, concentració de lligands adhesius. En un primer capítol, mostrem que el confinament dispara l’entrada de calci per mitjà de Piezo1. Això activa la fosfodiesterasa 1, que redueix els nivells d’AMPc i, en conseqüència, l’activitat PKARac1, que deixen d’inhibir Miosina II. També trobem una activació paral·lela de Miosina II directament per confinament. Com a resultat final, les cèl·lules guanyen rigidesa i optimitzen el seu mode migratori independent d’adhesions, que és el preponderant in vivo durant la invasió metastàtica. Reduir els nivells de Piezo1 suprimeix l’entrada de calci induïda per confinament i desactiva el circuit subjacent en cèl·lules ovàriques epitelials (CHO) i de melanoma (A375). Això minva la capacitat migratòria de les cèl·lules siPiezo1. En un segon capítol, descobrim un rol essencial per a Piezo2 com a activador de RhoA en resposta a estímuls mecànics. Això modula les respostes mecanobiològiques de les cèl·lules MDA-MB-231-BrM2, de càncer de mama metastàtic a cervell. La reducció dels nivells de Piezo2 destorba la formació de fibres d’estrès, l’orientació de les adhesions, la transmissió de forces i l’acumulació nuclear del regulador transcripcional prometastàtic YAP. Suprimir el calci extracel·lular fenocòpia aquests resultats. Promoure la polimerització d’Actina amb jasplaquinolida o mer mitjà de la sobreexpressió de formes constitutivament actives de RhoA o mDia1 restableix les fibres d’estrès i l’acumulació nuclear de YAP. A més, la reducció de Piezo2 suspèn diverses funcions prometastàtiques: proliferació cel·lular, migració, formació d’invadopodis, degradació de la matriu extracel·lular i secreció de SERPINB2, una proteïna necessària per protegir les cèl·lules invasores dels mecanismes de defensa del parènquima cerebral. Els treballs presentats en aquesta tesi desvelen rols importants pels canals Piezo com a una primera línia de detectors d’estímuls mecànics en diferents tipus cel·lulars. Aquests descobriments són rellevants per a diversos àmbits, com ara la recerca en càncer, i remarquen la importància dels canals iònics com a transductors d’estímuls ambientals.
Al-Rekabi, Zeinab. "Investigating Mechanotransduction and Mechanosensitivity in Mammalian Cells." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/30256.
Full textLammerding, Jan 1974. "Quantitative analysis of subcellular biomechanics and mechanotransduction." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/18039.
Full textIncludes bibliographical references.
Biological cells such as endothelial or muscle cells respond to mechanical stimulation with activation of specific intracellular and extracellular signaling pathways and cytoskeletal remodeling, a process termed mechanotransduction. Intracellular mechanosensors are thought to be activated by conformational changes induced by local cellular deformations. Since these mechanosensors have been speculated to be located in several cellular domains including the cell membrane, the cytoskeleton, and the nucleus, it is necessary to achieve a detailed understanding of subcellular mechanics. In this work, we present novel methods to independently quantify cytoskeletal displacements, mechanical coupling between the cytoskeleton and the extracellular matrix, and nuclear mechanics based on high resolution tracking of cellular structures and receptor bound magnetic beads in response to applied strain or microscopic forces. These methods were applied to study the effects of several human disease associated mutations on subcellular mechanics and to examine the interaction between known protein function and specific changes in cellular mechanical properties and mechanotransduction pathways. Initial experiments were targeted to the role of membrane adhesion receptors. Experiments with cells expressing a mutant form of the integrin-associated molecule tetraspanin CD151 revealed that CD151 plays a key role in selectively strengthening α6βl integrin-mediated adhesion to laminin-1. We then studied cytoplasmic behavior using cells from mice with an αB-Crystallin mutation (R120G) that causes desmin-related myopathy. These studies showed impaired passive cytoskeletal mechanics in adult mouse cardiac myocytes. Finally, we studied cells deficient in the nuclear envelope
(cont.) protein lamin A/C and showed that lamin A/C deficient cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain, suggesting that the tissue specific effects observed in laminopathies such as Emery-Dreifuss muscular dystrophy or Hutchinson-Gilford progeria may arise from varying degrees of impaired nuclear mechanics and transcriptional regulation. In conclusion, our methods provide new and valuable tools to examine the role of subcellular biomechanics on mechanotransduction in normal and mutant cells, leading to improved understanding of disease mechanisms associated with altered cell mechanics.
by Jan Lammerding.
Ph.D.
Pitts-Yushchenko, Svetlana. "Mechanism of mechanotransduction in the Pacinian corpuscle." Thesis, University of Exeter, 2013. http://hdl.handle.net/10871/15429.
Full textCappelli, Holly. "TRPV4 Mechanotransduction in Vascular Growth and Integrity." Kent State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=kent1487764322127302.
Full textLee, Herng-Sheng. "Integrin-mediated mechanotransduction in human articular chondrocytes." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23083.
Full textMiller, Gregory J. "Mechanoregulation and mechanotransduction in skeletal tissue differentiation." Thesis, Boston University, 2013. https://hdl.handle.net/2144/11147.
Full textMechanical factors play a critical role in the development, maintenance and repair of skeletal tissues. Mechanical stimulation can alter the course of healing by directing the differentiation of mesenchymal progenitor cells into the cells that form the various skeletal tissues, and can enhance or impair the repair of orthopaedic injuries. Several mechanoregulatory hypotheses describing the relationships between mechanical stimuli and skeletal tissue differentiation have been proposed; however, these hypotheses have not been fully tested, nor have the underlying mechanisms been established. Identification of the specific mechanical stimuli and molecular mechanisms that direct the differentiation of mesenchymal progenitor cells would provide insight for treating injuries. The focus of this dissertation was to further our understanding of the mechanobiology of skeletal tissue differentiation by identifying the mechanisms that regulate the differentiation of mesenchymal progenitor cells. The first part of this dissertation identified consistent associations between the patterns of the formation of skeletal tissues (bone, cartilage, fibrocartilage and fibrous tissues) and the magnitudes of strains (shear and principal strains) in a mechanically-stimulated bone defect in vivo. The second part of this dissertation found evidence that the Rho-family GTPases, as well as adhesion receptors and their associated focal adhesion proteins, may be possible mediators of the mechanotransduction mechanisms involved in the decisions of cell fate of the mesenchymal progenitor cells within the stimulated tissues. Finally, in an anticipation of the next steps in research on mechano-regulation of tissue differentiation, a microindentation technique was developed to determine the poroelastic material properties of the soft tissues forming in the callus. The values of Young's modulus, Poisson's ratio and permeability of articular cartilage were measured at the microscale and compared to those determined using standard macroscale techniques. Together, the findings of this dissertation further our understanding of the mechanoregulation of skeletal tissue differentiation, and can be used to inform and improve the various hypotheses regarding the mechanoregulation of tissue differentiation. Clinically, these results could potentially direct the development of therapies to improve treatment outcomes and reduce recovery time.
ULLOA, SEVERINO LUISA. "Mechanobiology and mechanotransduction in propathological cellular system." Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2919813.
Full textCells and tissues respond to environmental forces transducing them into biochemical signals. This cellular property has induced a large interest in biomedical area to study the possibility of using cell (or tissue) mechanical properties (e.g., their stiffness) as a marker for early diagnosis of pathologies or as trigger point to modulate cell/tissue behavior via new, ad hoc designed, prosthetic materials. In this thesis work I have shown that AFM could represent an excellent tool to evaluate the mechanical properties of different cellular systems. In particular, I have studied the biomechanics in the onset of calcific aortic valve disease, in the tumor associated p53 missense mutants and in myogenesis. Calcific aortic valve disease is the most common cardiomyopathy and is the main cause of aortic stenosis. The primary driver for valvular calcification is the differentiation of valvular interstitial cells (VICs) into a disease-associated phenotype. Another characteristic of this disease is the significant change in the organization, composition and mechanical properties of the ECM that beside being the result of the dysfunction of the valve cells. In this context, I have initially investigated on the variation of mechanical and morphological properties in hVICs when grown on flat polyacrylamide gels at different stiffness. I performed this task using both AFM force spectroscopy and molecular biology essays. My results show that there is a strong direct dependence of cellular rigidity by that of the underlying substrate, resembling a sort of flat matrix. In addition, I observed that inhibition of Rho kinase will result in a preclusion of actin polymerization followed by a reduced cellular stiffness and YAP activation. I have performed the same AFM characterisation on a more complex experimental model that involves thin sections of explanted stenotic calcific human valves. After this, I moved my studies on the effect of a nanostructured extra-cellular matrix like substrate could have on VICs. I did that taking advantage of multi-walled CNTs carpets grown on glass slides above which I subsequently seeded porcine Valvular Interstitial cells. Initially I performed a morphological characterization pointing out that CNTs have a positive effect on pVICs, in particular the myofibroblat percentage in VICs developed above CNTs is similar to that of a healthy valve. I performed cell stiffness measurements via AFM and I discovered that myofibroblast stiffness is not significantly altered by CNTs. I associated this result to the low density of focal adhesions expressed on these cells by the nanostructures substrate. At this point I could hypothesize that CNTs, piercing and pinching the plasma membrane, are able to facilitate the creation of clusters of FAs that, at the very end, will increase the cellular rigidity. Subsequently, I focused my studies to the mechanobiology of tumor associated p53 mutants. In this part of my work I studied the cellular processes and biochemical pathways stabilizing mutant p53 cells. I performed an AFM force spectroscopy characterization of cells after treatment with different drugs and I confirmed a stiffness reduction in treated cells determined by an actin de-polymerization process and a reduction of p53 levels. Following, I studied the same process in a ex vivo model taking advantage of AFM nano-indentation procedure. At the end of my thesis, I have characterized a new HELP family polypeptide, HELPc, synthetized at the University of Trieste. By characterizing HELPc coating and hydrogel via AFM imaging. Following, HELPc was used as a substrate for C2C12 myoblasts growth. The results showed that the addition of a sequence to from the α2 isoform of collagen type IV, containing to RGD motives, determines an improve of cells activity by combining several methods, as immunofluorescence, Atomic Force Microscopy and Ca2+ imaging.
Shin, Jung-Bum. "Identification of genes involved in sensory neuron mechanotransduction." [S.l. : s.n.], 2002. http://www.diss.fu-berlin.de/2003/68/index.html.
Full textJokl, Elliot. "Mechanotransduction at the Z-disc of skeletal muscle." Thesis, University of York, 2017. http://etheses.whiterose.ac.uk/19324/.
Full textKarcher, Hélène. "The mechanics of mechanotransduction : analyses of cell perturbation." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/38239.
Full textIncludes bibliographical references.
Cells sense mechanical stimuli and respond by changing their phenotype, e.g. shape, gene expression, motility. This process, termed mechanotransduction, was investigated using computational and theoretical approaches, as well as comparisons with experiments. As a first step, a three-dimensional viscoelastic finite element model was developed to simulate cell micromanipulation by magnetocytometry. The model provided a robust tool for analysis of detailed strain/stress fields induced within a single cell or cell monolayer produced by forcing one tethered microbead. On the assumption of structural homogeneity, stress and strain patterns were highly localized, suggesting that the effects of magnetocytometry are confined to a region extending less than 10tm from the bead. Modification of the model to represent experimental focal adhesion attachments supported a non-uniform force transmission to basal surface focal adhesion sites. Proteins in identified zones of high stresses in the cell are candidate mechanosensors and their molecular response to force was hence investigated, A generic model of protein extension under external forcing was created inspired by Kramers theory for reaction rate kinetics in liquids.
(cont.) The protein was hypothesized to have two distinct conformational states: a relaxed state, Ci, preferred in the absence of external force, and an extended state, C2, favored under force application. Appearance and persistence of C2 was assumed to lead to transduction of the mechanical signal into a chemical one. While the level of applied force and the energy difference between states largely determined equilibrium, the dominant influence on the extension time was the height of the transition state. Force-induced distortions in the energy landscape were also shown to have a significant influence on extension time, however, exhibiting a weaker force dependence than exponential. Finally, the link between membrane receptors and the extracellular matrix -- or the bead in magnetocytometry experiments -- was investigated as a primary path for force transduction to the cell interior. To shed light on the role of bonds formed by membrane receptors on measurements of cellular rheology, we modeled the process by which a forced, cell-tethered microbead translates and rotates as influenced by the stochastic formation and. rupture of adhesion bonds. We show that this process is crucial in the inference of cell mechanical properties from microbead experiments.
by Hélène Karcher.
Ph.D.
McVittie, Anna K. (Anna Kathleen) 1977. "Pathways for mechanotransduction in pressurized airway epithelial cells." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/89315.
Full textDrew, Liam John. "Mechanisms of mechanotransduction by dorsal root ganglia neurons." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446740/.
Full textMcNamara, Laura Elizabeth. "Molecular and cellular analysis of topography-induced mechanotransduction." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2207/.
Full textDahl, Anna Caroline E. "Membrane protein mechanotransduction : computational studies and analytics development." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:67798647-8ed5-46e0-bde9-c71235fe70ba.
Full textHeayn, Michelle Diane. "The Role of Caveolae in PECAM-1 Mechanotransduction." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/263778.
Full textPh.D.
Altered fluid flow, which is found in branches and curvatures of arteries, results in abnormal forces on the endothelial cells (EC). These forces have been shown to alter EC gene expression and phenotype and to activate several cellular structures including G-proteins, ion channels, adhesion molecules, and caveolae. Recently, PECAM-1 has been implicated as the primary sensor of hemodynamic forces in EC. Shear stress rapidly induces tyrosine phosphorylation of PECAM-1 and the recruitment of SHP-2. These events appear to contribute to shear-activation of ERK1/2. Additionally, PECAM-1 has been shown to form a mechanosensory signaling complex with VE-cadherin, VEGFR2, and βcatenin which plays a role in adhesion molecule expression and regulation of NF-κB. Past work has shown that caveolae membrane domains also serve as mechanotransduction sites that regulate many of these same second messengers. Based on these novel observations, we hypothesize that the PECAM-1 mediated mechanotransduction requires caveolar membrane domains to effectively propagate mechano-signals. In this study, we intended to specifically test this hypothesis by 1) evaluating the role of caveolae in shear stress-induced PECAM-1 tyrosine phosphorylation, recruitment of SHP-2, and formation of a signaling complex with VE-cadherin, VEGFR2, and βcatenin and 2) determining the functional significance of PECAM-1 compartmentalization within caveolae with regard to changes in endothelial cell phenotype induced by atherogenic patterns of flow. Here, we have identified a pool of PECAM-1 which localizes within lipid rafts and caveolar membranes. This pool of PECAM-1 was shown to be activated by tyrosine phosphorylation and recruitment of mechanosignaling complex members in response to shear stress. We were also able to demonstrate complex formation in an in vivo model of disturbed blood flow. The significance of PECAM-1 compartmentalization to these membrane microdomains was demonstrated in endothelial cells treated with raft/caveolae disrupting compounds where shear stress-induced PECAM-1 tyrosine phosphorylation was markedly attenuated. Finally, we attempted to generate an adenovirus expressing a mutant form of PECAM-1 which was unable to target to lipid rafts in order to determine the importance of PECAM-1 localization in lipid rafts and caveolae on its downstream signaling in response to shear stress. Results from these studies provide new knowledge as to how endothelial cells respond to changing hemodynamic parameters, which could provide greater insight into how flow influences vascular homeostasis.
Temple University--Theses
FARRIS, FRANCESCO. "AMYLOID FIBRILS INDUCE GLYCOCALYX MEDIATED MECHANOTRANSDUCTION IN MELANOMA." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/946381.
Full textSchwartz, Christine. "Muscle LIM protein and Nesprin-1 in Mechanotransduction." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066374/document.
Full textI studied three striated muscle proteins that are participating in two different pathways of mechanotransduction, which is the translation of a physical stimulus into a biochemical signal.When isolated cardiomyocytes are stretched in 2D, MLP shuttles to the nucleus. Without shuttling MLP, these cells fail to respond to the stretch stimulus. Human patients with MLP-mutations develop cardiomyopathies, as well as mice with a knock-out of MLP (MLP-/-). By expressing mutated MLP in neonatal cardiomyocytes of MLP-/- mice, I wanted to elucidate the role of mutant MLP. Surprisingly, MLP did shuttle after stretching of 2D but not 3D cell cultures. Although I could not solve this issue, I prepared the setup for subsequent experiments.Nesprins are part of the nuclear envelope (NE) spanning LINC complex, which connects the cytoskeleton with the nucleus. Myoblasts from patients with mutations in Nesprins or LINC-associated Lamins displayed deformed nuclei and had defects in mechanosensitive responses with an elevated level of stress fibers and focal adhesions on soft surfaces. This phenotype could be rescued by knock-down of formin FHOD1, a downstream target of ROCK and SRC, which also were highly active in the mutant cells. While mutations in Nesprins and Lamins are thought to lead to mechanical instability of the NE, these results indicate that signaling pathways through the NE are disturbed as well
Schwartz, Christine. "Muscle LIM protein and Nesprin-1 in Mechanotransduction." Electronic Thesis or Diss., Paris 6, 2016. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2016PA066374.pdf.
Full textI studied three striated muscle proteins that are participating in two different pathways of mechanotransduction, which is the translation of a physical stimulus into a biochemical signal.When isolated cardiomyocytes are stretched in 2D, MLP shuttles to the nucleus. Without shuttling MLP, these cells fail to respond to the stretch stimulus. Human patients with MLP-mutations develop cardiomyopathies, as well as mice with a knock-out of MLP (MLP-/-). By expressing mutated MLP in neonatal cardiomyocytes of MLP-/- mice, I wanted to elucidate the role of mutant MLP. Surprisingly, MLP did shuttle after stretching of 2D but not 3D cell cultures. Although I could not solve this issue, I prepared the setup for subsequent experiments.Nesprins are part of the nuclear envelope (NE) spanning LINC complex, which connects the cytoskeleton with the nucleus. Myoblasts from patients with mutations in Nesprins or LINC-associated Lamins displayed deformed nuclei and had defects in mechanosensitive responses with an elevated level of stress fibers and focal adhesions on soft surfaces. This phenotype could be rescued by knock-down of formin FHOD1, a downstream target of ROCK and SRC, which also were highly active in the mutant cells. While mutations in Nesprins and Lamins are thought to lead to mechanical instability of the NE, these results indicate that signaling pathways through the NE are disturbed as well
Chowdhury, Tina Taneer. "Role of nitric oxide and PGEâ‚‚ in chondrocyte mechanotransduction." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246308.
Full textLiao, Pinhu. "Mechanotransduction in alveolar epithelial cells subjected to mechanical strain." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479153.
Full textLiu, Jie. "Mechanotransduction in Endothelial Cells:Cell Growth, Angiogenesis and Wound Healing." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274392778.
Full textBalasubramanian, Lavanya. "Integrin Mediated Mechanotransduction in Renal Vascular Smooth Muscle Cells." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002227.
Full textSummerour, Sonya R. "Static equibiaxial stretch mediated mechanotransduction in adult cardiac fibroblasts /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9952652.
Full textVanderploeg, Eric James. "Mechanotransduction in Engineered Cartilaginous Tissues: In Vitro Oscillatory Tensile Loading." Diss., Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-05192006-110158/.
Full textRadhakrishna, Harish, Committee Member ; LaPlaca, Michelle, Committee Member ; Nerem, Robert, Committee Member ; Garcia, Andres, Committee Member ; Levenston, Marc, Committee Chair.
Lian, Ian Yu-Zen. "The roles of E-Tmod in mechanotransduction and cardiac myofibrillogenesis." 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?p3249659.
Full textTitle from first page of PDF file (viewed March 23, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 123-134).
Schwartz, Christine [Verfasser]. "Muscle LIM Protein and Nesprin-1 in Mechanotransduction / Christine Schwartz." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/112815062X/34.
Full textFitzgerald, Jonathan Basil. "Chondrocyte gene expression and intracellular signaling pathways in cartilage mechanotransduction." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33869.
Full textIncludes bibliographical references (p. 152-167).
Chondrocytes respond to in vivo mechanical loads by regulating the composition of the cartilage extracellular matrix. This study utilized three loading protocols that span the range of forces and flows induced by in vivo loading. Constant (static) compression of cartilage explants induces a transient hydrostatic pressure buildup and fluid exudation from the compacted matrix until relaxation leads to a new equilibrium compressed state. Dynamic compression induces cyclic matrix deformation, hydrostatic pressures, fluid flows, and streaming currents. Dynamic tissue shear causes cyclic matrix deformation only. After applying these loading protocols to intact cartilage explants for 1 to 24 hours, we used real-time PCR to measure the temporal expression profiles of selected genes associated with cartilage homeostasis. In concurrent experiments, we assessed the involvement of intracellular signaling pathways using molecular inhibitors. In order to interpret the results we developed two techniques that reliably clustered intermediate-sized datasets using principal component analysis and k-means clustering. Mechanical loading regulated a variety of genes including matrix proteins, proteases, protease inhibitors, transcription factors, cytokines, and growth factors. Static compression transiently upregulated matrix proteins, however, mRNA levels were suppressed by 24 hours.
(cont.) Dynamic compression and dynamic shear increased matrix protein transcription particularly after 24 hours. In contrast, matrix proteases were upregulated by all 24 hour loading regimes, particularly static compression. Taken together these results demonstrate the functionally-coordinated regulation of chondrocyte gene transcription in response to mechanical forces, and support the hypothesis that dynamic loading is anabolic for cartilage and static loading is anti-anabolic. Intracellular calcium release, cAMP activation of protein-kinase-A, and the phosphorylation of MAP kinases (ERK1/2, p38), were all identified as signaling events necessary for mechanically-induced transcription. In addition, we measured the immediate, transient increase in mRNA levels of transcription factors downstream of the MAP kinase pathway (c-Fos and c-Jun), in response to all three loading types. The prevention of protein synthesis during static compression suppressed mechanically-induced transcription suggesting that signaling molecules are synthesized in response to mechanical forces. Comparison of this well characterized model of normal cartilage mechanotransduction to what occurs within diseased cartilage will hopefully provide insight into the mechanisms driving the progression of osteoarthritis.
by Jonathan Basil Fitzgerald.
Ph.D.
Rabodzey, Aleksandr. "Flow-induced mechanotransduction in cell-cell junctions of endothelial cells." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/41586.
Full textIncludes bibliographical references (leaves 86-92).
Endothelial cells show an unexpected behavior shortly after the onset of laminar flow: their crawling speed decreases ~40% within the first 30 min, but only in a confluent monolayer of endothelial cells, not in subconfluent cultures, where cell-cell interactions are limited. This led us to study early shear effects on cell-cell adherens junctions. We found a 30±6% increase in the number of VE-cadherin molecules in the junctions. The strength of interactions of endothelial cells with surfaces coated with recombinant VE-cadherin protein also increased after laminar flow. These observations suggest that endothelial cell junction proteins respond to flow onset. The process of clustering may induce diffusion of monomers to the junction area, resulting in an overall increase in VE-cadherins in the junctions. To directly confirm the role of adherens junctions in the decrease in cell crawling speed, we used siRNA-knockdown technique to produce cells lacking VE-cadherin. These cells showed no decline in crawling speed under flow. Our interpretation is consistent with previous data on junction disassembly 8 hr after flow onset. The speed of endothelial cell crawling returns to the original level by that time, and junctional disassembly may explain that phenomenon. In order to understand better the change in VE-cadherin distribution under flow and during junction formation and remodelling, we developed a mathematical model of VE-cadherin redistribution in endothelial cells. This model allowed us to develop a quantitative framework for analysis of VE-cadherin redistribution and estimate the amount of protein in the junctions and on the apical surface. In addition to that, the model explains rapid junction disassembly in the leukocyte transmigration and junction formation in subconfluent cells.
(cont.) These studies show that intercellular adhesion molecules are important in the force transmission and shear stress response. Their role, however, is not limited to flow mechanotransduction. Intercellular force transmission has an important application - organ development and, specifically, angiogenesis. We studied the role of VE-cadherin in vessel development in HUVECs and showed that VE-cadherin-null cells do not form vessels in the in vitro assay. This observation confirms the important role of intercellular force transmission in response to external force caused by flow or exerted by other cells.
by Aleksandr Rabodzey.
Ph.D.
Kojić, Nikola 1978. "Mechanotransduction via airway epithelial cells : the effect of compressive stress." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/40870.
Full text"June 2007."
Includes bibliographical references (leaves 153-157).
A classic finding in asthma is a change in the structural organization of the airway epithelium. This complex process known as airway remodeling is not fully understood, and we believe that the forces accompanying airway constriction activate the epithelium and contribute to airway remodeling. To better understand this mechanotransduction mechanism we used an in vitro system of cultured normal human bronchial epithelial cells that could simulate compressive stresses experienced by the epithelium during bronchoconstriction. The application of a transcellular pressure gradient (10-50cmH20) for 10 minutes resulted in transient activation of the epidermal growth factor receptor (EGFR) - MAP kinase (ERK) signaling pathway. Furthermore, specialized real-time high-speed imaging revealed an exponential decrease in the volume of the compliant lateral intercellular space (LIS) separating neighboring cells. The measured LIS volume collapse curves were directly inputted into 2-D and 3-D numerical finite element models, whose output was EGFR-ligand concentration dynamics in the LIS.
(cont.) During the first three minutes under pressure, the calculated increase in ligand concentration (specifically HB-EGF, which is made by the cells and shed into the LIS, thereby constituting an autocrine loop with the EGFR) matched the measured phosphorylated EGFR (pEGFR) dynamics. The model thus provided crucial insight into how an observed change in LIS geometry esulted in activation of the EGFR signaling pathway. This insight, coupled to EGFR signaling models, could one day be applied to the design of novel pharmacogenetic therapeutics aimed at preventing airway over-activation and potentially hindering airway remodeling progression in asthmatic patients.
by Nikola Kojić.
Ph.D.
Jonas, Maxine. "Fluorescence laser tracking microrheology for quantitative studies of cytoskeletal mechanotransduction." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39911.
Full textIncludes bibliographical references (p. 111-127).
To shed light on the cell's response to its mechanical environment, we examined cell rheology at the single cell level and quantified it with nanometer spatial and microsecond temporal resolutions over a five-decade frequency range (- 0.5 Hz to 50 kHz). To this end, we developed and optimized an instrument for fast fluorescence laser tracking microrheology (FLTM). This novel method aims at experimentally deriving cellular viscoelastic properties from the passive monitoring of fluorescent microspheres undergoing Brownian motion inside the tested sample. Further instrument enhancement even broadens the FLTM frequency span up to seven decades by modulating data acquisition speed or complementing FLTM with a two-particle microrheology modality. In living cells, FLTM accurately characterizes the solid-like vs. liquid-like cytoskeletal behavior from measurements based on endocytosed micron-sized beads, independently of probe size or surface chemistry. FLTM also demonstrates the existence of two distinct rheological regimes on the cell surface and in the cell interior: While the former surface investigations show power-law frequency variations of the complex shear modulus G*(co), the latter intracellular experiments identify multiple time and length scales affecting cell rheological features. Finally, FLTM evaluates frequency-specific stretch-induced cell mechanics and thus promises to broaden and diversify the scientific knowledge on mechanotransduction, from a molecular and cellular standpoint.
(cont.) FLTM also demonstrates the existence of two distinct rheological regimes on the cell surface and in the cell interior: While the former surface investigations show power-law frequency variations of the complex shear modulus G*(co), the latter intracellular experiments identify multiple time and length scales affecting cell rheological features. Finally, FLTM evaluates frequency-specific stretch-induced cell mechanics and thus promises to broaden and diversify the scientific knowledge on mechanotransduction, from a molecular and cellular standpoint.
by Maxine Jonas.
Ph.D.
Mahajan, Kalpesh D. "Development of Nanodevices for Bio-detection, Separation, Therapy, and Mechanotransduction." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376446892.
Full textServin, Vences Martha Rocio [Verfasser]. "Ion-channel mediated mechanotransduction in chondrocytes / Martha Rocio Servin Vences." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1154766608/34.
Full textChilds, Peter Geoffrey. "Cellular mechanotransduction : development of a nanovibrational bioreactor for cellular stimulation." Thesis, University of the West of Scotland, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.739388.
Full textSaini, Navpreet S. "Cell Type and Substrate Dependence of Fibronectin Properties and Mechanotransduction." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5806.
Full textFulzele, Keertik S. "ROLE OF ACTIN CYTOSKELETON FILAMENTS IN MECHANOTRANSDUCTION OF CYCLIC HYDROSTATIC PRESSURE." MSSTATE, 2004. http://sun.library.msstate.edu/ETD-db/theses/available/etd-07122004-171347/.
Full textRoberts, Susan Read. "Mechanotransduction pathways associated with intracellular calcium in chondrocytes within 3D constructs." Thesis, Queen Mary, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270626.
Full textPolacheck, William J. (William Joseph). "Mechanotransduction of interstitial fluid stresses and effects on tumor cell migration." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/85531.
Full text"September 2013." Cataloged from PDF version of thesis.
Includes bibliographical references (pages 93-106).
Breast cancer incidence in the United States is I in 8, and over 90% of breast cancer related deaths are due to metastases, secondary tumors at a site distant from the primary tumor. Metastasis formation requires carcinoma cells to navigate through the tumor microenvironment and invade the surrounding stroma. Migration is a highly orchestrated process in which cells are guided by both internal signals and signals from the microenvironment. Hence, understanding the mechanisms that guide cell migration in response to various stimuli in the tumor and stromal microenvironments is key to developing therapies that prevent tumor cell migration and render cancer more treatable. Osmotic and hydrostatic pressure gradients within the extracellular matrix (ECM) drive flow of interstitial fluid through the ECM. Elevated osmotic pressure, lymphatic collapse, solid stress, and increased microvascular permeability contribute to elevated interstitial fluid pressure (IFP) during carcinoma progression, and high intratumoral IFP leads to pressure gradients at the tumor margin, which drive fluid flow that emanates from the tumor core to drain in the surrounding stroma. In this thesis, we explore the effect of interstitial flow (IF) on tumor cell migration. We developed a microfluidic platform to apply repeatable, robust IF through tissue constructs consisting of human metastatic breast cancer cells embedded within a 3D collagen type I matrix. We implemented the microfluidic device to validate CCR7-mediated autologous chemotaxis as a mechanism that guides downstream migration in response to IF. However, we identified a separate competing pathway that drives cell migration upstream (rheotaxis). Rheotaxis results from asymmetry in matrix adhesion stress that is required to balance fluid drag imparted by IF on tumor cells. Thus, autologous chemotaxis, mediated by chemical transport, and rheotaxis, mediated by fluid stresses, compete to direct cell migration downstream or upstream in response to IF. Our results provide insight into mechanotransduction in 3D porous media and into the mechanisms by which asymmetries in matrix adhesion tension guide cell migration. Furthermore, our results demonstrate that the consideration of IF is crucial for understanding and treating metastatic disease. Key words: Interstitial flow, mechanotransduction, tumor cell migration, microfluidics.
by William J. Polacheck.
Ph. D.
Patel, Sagar. "THE MECHANOTRANSDUCTION OF PRIMARY CILIA IN TUMOR PROGRESSION OF LUNG ADENOCARCINOMA." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3071.
Full textStephenson, Natalie. "Mechanotransduction of the Notch signalling pathway via the negative regulatory region." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/mechanotransduction-of-the-notch-signalling-pathway-via-the-negative-regulatory-region(c13c0f01-3095-4895-a536-1dfc324d9899).html.
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