Mutations in the nuclear envelope proteins lamins A and C cause Emery-Dreifuss muscular dystrophy, limbgirdle muscular dystrophy, and a broad spectrum of other diseases collectively called laminopathies. The underlying disease mechanism is unclear, but recent evidence suggests that disrupted nuclear-cytoskeletal coupling could contribute to the muscular phenotypes. Lamins A and C are required for the correct nuclear envelope localization of the LINC complex, which connects the nucleus to the cytoskeleton, but the effects of specific lamin A/C mutations remain unclear. My long term goal is to understand if lamin A/C mutations can disturb nuclear-cytoskeletal coupling through the LINC complex, resulting in abnormal intracellular force transmission and mechanotransduction that could contribute to the tissue specific phenotypes in muscular laminopathies, similar to the disease etiology of Duchenne muscular dystrophy.
My specific aims are: ? 1. To test the hypothesis that the LINC complex is required for force transmission from the cytoskeleton to the nucleus. I will measure nuclear deformation in response to applied cytoskeletal strain after selective disruption of the LINC complex with dominant negative mutants or gene silencing by RNA interference. ? 2. To test the hypothesis that specific lamin A/C mutations can LINC complex localization to the nuclear envelope. I will analyze intracellular distribution and diffusional mobility of LINC complex components in cells from laminopathy patients, mouse models of muscular laminopathies, and healthy/wild-type controls. ? 3. To test the hypothesis that lamin A/C mutations can alter force transmission through the LINC complex, have designed a novel magnetic bead adhesion assay to quantify the maximal force that can be transmitted through the LINC complex and I will apply this technique to cells carrying specific lamin A/C mutations. ? 4. To test the hypothesis that disruption of the LINC complex alters mechanotransduction. I will measure strain-induced gene expression in cells in which LINC complex function has been selectively disrupted. ? Studying the effect of lamin A/C mutations on nuclear-cytoskeletal coupling will help to improve our understanding of normal and tissue-specific functions of the nuclear envelope and can lead to new insights into the molecular mechanisms responsible for muscular laminopathies such as Emery-Dreifuss muscular dystrophy, potentially providing new targets for the treatment of these diseases. ? ? ?
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| Fedorchak, Gregory; Lammerding, Jan (2016) Cell Microharpooning to Study Nucleo-Cytoskeletal Coupling. Methods Mol Biol 1411:241-54 |
| Bell, Emily S; Lammerding, Jan (2016) Causes and consequences of nuclear envelope alterations in tumour progression. Eur J Cell Biol 95:449-464 |
| McGregor, Alexandra Lynn; Hsia, Chieh-Ren; Lammerding, Jan (2016) Squish and squeeze-the nucleus as a physical barrier during migration in confined environments. Curr Opin Cell Biol 40:32-40 |
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| Dialynas, George; Shrestha, Om K; Ponce, Jessica M et al. (2015) Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway. PLoS Genet 11:e1005231 |
| Mitchell, Michael J; Denais, Celine; Chan, Maxine F et al. (2015) Lamin A/C deficiency reduces circulating tumor cell resistance to fluid shear stress. Am J Physiol Cell Physiol 309:C736-46 |
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| Davidson, Patricia M; Lammerding, Jan (2014) Broken nuclei--lamins, nuclear mechanics, and disease. Trends Cell Biol 24:247-56 |
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