Emerin and inherited disease

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2004. === Includes bibliographical references (p. 54-55). === (cont.) nucleus and at the nuclear surface. === Mutations in the lamin A/C gene (Lmna) and the lamin-associated protein emerin gene (EM) cause a variety of human di...

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Main Author: Hsiao, Janet, 1981-
Other Authors: Richard Lee.
Format: Others
Language:en_US
Published: Massachusetts Institute of Technology 2005
Subjects:
Online Access:http://hdl.handle.net/1721.1/28759
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spelling ndltd-MIT-oai-dspace.mit.edu-1721.1-287592019-05-02T15:41:21Z Emerin and inherited disease Hsiao, Janet, 1981- Richard Lee. Harvard University--MIT Division of Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology. Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2004. Includes bibliographical references (p. 54-55). (cont.) nucleus and at the nuclear surface. Mutations in the lamin A/C gene (Lmna) and the lamin-associated protein emerin gene (EM) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy, Charcot-Marie-Tooth Neuropathy and Hutchinson-Gilford progeria syndrome. The molecular mechanisms underlying the varied phenotypes are unknown, and both a mechanical stress hypothesis and an altered gene expression hypothesis have been proposed to explain the tissue specific effects observed in laminopathies. To investigate the role of emerin in mechanotransduction, lamin A/C deficient (Lmna⁻/⁻) fibroblasts, and emerin deficient (EM⁻/y) fibroblasts were studied for nuclear mechanical properties, cytoskeletal stiffness, and mechanical strain-induced signaling. EM⁻/y fibroblasts exhibited similar cell sensitivity, nuclear and cytoskeletal properties compared to wild type cells under stress and strain. Interestingly, both Lmna⁻/⁻ and EM⁻/y fibroblasts had impaired mechanotransduction, characterized by attenuated expression of the mechanosensitive genes egr-1, iex-1, and txnip in response to mechanical stimulation. In addition, NF-rB signaling appeared disturbed in Lmna⁻/⁻ cells, but normal in EM⁻/y fibroblasts. The relationship between changes in cytoskeletal stiffness recently discovered in Lmna⁻/⁻ cells and nuclear mechanics under strain was explored using a computational finite elemental model. Analysis of the several models using variations in material properties and cell geometry revealed that nuclear shape, material properties of the cytoskeleton and nucleus, as well as the size and location of strain application on the cell are important parameters in determining the magnitude of stress and strain within the by Janet Hsiao. M.Eng. 2005-09-27T18:11:40Z 2005-09-27T18:11:40Z 2004 2004 Thesis http://hdl.handle.net/1721.1/28759 59823266 en_US 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. http://dspace.mit.edu/handle/1721.1/7582 71 p. 3831344 bytes 3838379 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology
collection NDLTD
language en_US
format Others
sources NDLTD
topic Harvard University--MIT Division of Health Sciences and Technology.
spellingShingle Harvard University--MIT Division of Health Sciences and Technology.
Hsiao, Janet, 1981-
Emerin and inherited disease
description Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2004. === Includes bibliographical references (p. 54-55). === (cont.) nucleus and at the nuclear surface. === Mutations in the lamin A/C gene (Lmna) and the lamin-associated protein emerin gene (EM) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy, Charcot-Marie-Tooth Neuropathy and Hutchinson-Gilford progeria syndrome. The molecular mechanisms underlying the varied phenotypes are unknown, and both a mechanical stress hypothesis and an altered gene expression hypothesis have been proposed to explain the tissue specific effects observed in laminopathies. To investigate the role of emerin in mechanotransduction, lamin A/C deficient (Lmna⁻/⁻) fibroblasts, and emerin deficient (EM⁻/y) fibroblasts were studied for nuclear mechanical properties, cytoskeletal stiffness, and mechanical strain-induced signaling. EM⁻/y fibroblasts exhibited similar cell sensitivity, nuclear and cytoskeletal properties compared to wild type cells under stress and strain. Interestingly, both Lmna⁻/⁻ and EM⁻/y fibroblasts had impaired mechanotransduction, characterized by attenuated expression of the mechanosensitive genes egr-1, iex-1, and txnip in response to mechanical stimulation. In addition, NF-rB signaling appeared disturbed in Lmna⁻/⁻ cells, but normal in EM⁻/y fibroblasts. The relationship between changes in cytoskeletal stiffness recently discovered in Lmna⁻/⁻ cells and nuclear mechanics under strain was explored using a computational finite elemental model. Analysis of the several models using variations in material properties and cell geometry revealed that nuclear shape, material properties of the cytoskeleton and nucleus, as well as the size and location of strain application on the cell are important parameters in determining the magnitude of stress and strain within the === by Janet Hsiao. === M.Eng.
author2 Richard Lee.
author_facet Richard Lee.
Hsiao, Janet, 1981-
author Hsiao, Janet, 1981-
author_sort Hsiao, Janet, 1981-
title Emerin and inherited disease
title_short Emerin and inherited disease
title_full Emerin and inherited disease
title_fullStr Emerin and inherited disease
title_full_unstemmed Emerin and inherited disease
title_sort emerin and inherited disease
publisher Massachusetts Institute of Technology
publishDate 2005
url http://hdl.handle.net/1721.1/28759
work_keys_str_mv AT hsiaojanet1981 emerinandinheriteddisease
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