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Quantitative analysis of subcellular biomechanics and mechanotransduction

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dc.contributor.advisor Roger Kamm and Richard Lee. en_US
dc.contributor.author Lammerding, Jan, 1974- en_US
dc.contributor.other Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.date.accessioned 2005-06-02T19:44:03Z
dc.date.available 2005-06-02T19:44:03Z
dc.date.copyright 2004 en_US
dc.date.issued 2004 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/18039
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2004. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract 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 en_US
dc.description.abstract (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. en_US
dc.description.statementofresponsibility by Jan Lammerding. en_US
dc.format.extent 2 v. (283 leaves) en_US
dc.format.extent 15809434 bytes
dc.format.extent 15847632 bytes
dc.format.mimetype application/pdf
dc.format.mimetype application/pdf
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri http://dspace.mit.edu/handle/1721.1/7582
dc.subject Biological Engineering Division. en_US
dc.title Quantitative analysis of subcellular biomechanics and mechanotransduction en_US
dc.type Thesis en_US
dc.description.degree Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.identifier.oclc 57350875 en_US


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