Hutchinson-Gilford progeria syndrome (HOPS) is a rare genetic disorder characterized by dramatic premature aging. Patients with HGPS appear normal at birth, but begin to display alopecia, growth retardation, bone abnormalities, osteoporosis, and sclerodermatous skin by one year of age. On average, death occurs at the age of 12 from heart attack or stroke. Classic HGPS is caused by a de novo point mutation in exon 11 (1824, C->T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A protein termed "progerin" that lacks the normal cleavage site to remove a C-terminal farnesyl group. My long-term research objective is to uncover the cellular mechanisms underlying HGPS and normal aging.
In specific aim 1, we propose to analyze the defects caused by progerin and identify progerin interacting partners. A cohnbined cellular biological and biochemical approaches will be taken to achieve this aim.
In specific aim 2, we will investigate the role of progerin in the normal aging process. We propose that progerin is produced in normal cells, and is causatively associated with senescence of those cells that express it. To test this idea, we will investigate how progerin is produced in the normal cells, and the functional relationship between jsrogerin and normal aging.
In specific aim 3, we propose to generate highresolution, genome-wide maps of the alterations of chromatin structure and gene expression in HGPS cells using an approach that couples chromatin immunoprecipitation with next-generation sequencing (ChlP-seq) as well as gene expression analysis. Data from these high-throughput analysis will provide valuable information on when and how the changes of chromatin structure happen in HGPS cells, and which essential genes/pathways are affected in HGPS cells.

Public Health Relevance

The proposed studies will significantly improve our current understanding of the cellular mechanisms of HGPS and normal aging. The high-resolution map of the alterations in epigenetic modifications and gene expression in HGPS will provide an initial framework for detailed analysis of potentially important genes/pathways involved in HGPS and normal aging, which may also provide valuable information for future clinical treatments of HGPS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
5R00AG029761-04
Application #
8320210
Study Section
Special Emphasis Panel (NSS)
Program Officer
Velazquez, Jose M
Project Start
2010-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$285,299
Indirect Cost
$77,671
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Zhang, Haoyue; Xiong, Zheng-Mei; Cao, Kan (2014) Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci U S A 111:E2261-70
Wu, Di; Flannery, Andrew R; Cai, Helen et al. (2014) Nuclear localization signal deletion mutants of lamin A and progerin reveal insights into lamin A processing and emerin targeting. Nucleus 5:66-74
McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue et al. (2013) Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res 23:260-9
Xiong, Zheng-Mei; LaDana, Christina; Wu, Di et al. (2013) An inhibitory role of progerin in the gene induction network of adipocyte differentiation from iPS cells. Aging (Albany NY) 5:288-303
Candia, Julian; Maunu, Ryan; Driscoll, Meghan et al. (2013) From cellular characteristics to disease diagnosis: uncovering phenotypes with supercells. PLoS Comput Biol 9:e1003215
Zhang, Haoyue; Kieckhaefer, Julia E; Cao, Kan (2013) Mouse models of laminopathies. Aging Cell 12:2-10
Driscoll, Meghan K; Albanese, Jason L; Xiong, Zheng-Mei et al. (2012) Automated image analysis of nuclear shape: what can we learn from a prematurely aged cell? Aging (Albany NY) 4:119-32
Cao, Kan; Blair, Cecilia D; Faddah, Dina A et al. (2011) Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J Clin Invest 121:2833-44
Cao, Kan; Graziotto, John J; Blair, Cecilia D et al. (2011) Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med 3:89ra58
Olive, Michelle; Harten, Ingrid; Mitchell, Richard et al. (2010) Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol 30:2301-9