Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature senescence. Affected children appear normal at birth, but within a year develop characteristic features of old age. The majority of HGPS children die from cardiac disease at an average age of 13 years. Genetic studies have identified a mutation in the lamin A/C (LMNA) gene in 18 classical HGPS cases. The mutation results in the production of a mutant lamin A protein with an internal deletion. The mechanism by which the mutated HGPS lamin A protein leads to accelerated aging is unknown. Lamin A appear to maintain nuclear structure and function through a set of specific protein interaction with other cellular factors. I therefore hypothesize that expression of the mutant HGPS lamin-A protein results in premature aging as a consequence of the altered composition and function of lamin A-containing complexes within the nucleus. To test this hypothesis, in Aim 1 I will first define the cellular growth properties of HGPS fibroblast to identify the cellular pathways responsible for the limited life span of these cells in culture. Then in aim 2, I will employ biochemical approaches to identify and characterize the proteins associated with wild type and mutant HGPS lamin A. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM076861-02
Application #
7168228
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$40,831
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Candelario, Jose; Chen, Leng-Ying; Marjoram, Paul et al. (2012) A filtering strategy identifies FOXQ1 as a potential effector of lamin A dysfunction. Aging (Albany NY) 4:567-77
Candelario, Jose; Borrego, Stacey; Reddy, Sita et al. (2011) Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis. Exp Cell Res 317:319-29