Mutations in the inner nuclear membrane protein lamin A/C gene cause a variety of human diseases including dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and Hutchinson-Gilford progeria syndrome. One of the fascinating questions about these diseases is why different mutations in a single gene can cause such diverse phenotypes. The tissue specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined. Preliminary data showed that fibroblasts derived from lamin A/C deficient mice are characterized by impaired nuclear and cytoskeletal mechanics as well as mechanically and cytokine induced gene regulation. To further address the mechanisms of pathophysiology of specific mutations affecting the nuclear membrane, two hypothesis-driven aims are proposed: ? Aim 1: To explore the mechanisms of specific mutations in lamin A/C that lead to different phenotypes observed in laminopathies.
Aim 2 : To explore tissue specific effects of lamin A/C and specific mutations using cells derived from different tissue types, including cardiac myocytes, skeletal myoblasts, adipocytes and fibroblasts. ? ? ?
| Verstraeten, Valerie L R M; Ji, Julie Y; Cummings, Kiersten S et al. (2008) Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 7:383-93 |
| Ji, Julie Y; Lee, Richard T; Vergnes, Laurent et al. (2007) Cell nuclei spin in the absence of lamin b1. J Biol Chem 282:20015-26 |
