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Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the dramatic, rapid appearance of aging beginning in childhood. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive).
My laboratory is interested in why and how we age. Specifically, we focus on studying molecular mechanisms of Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disease, and exploring the potential connections betweenHGPS and normal aging. Children with HGPS die at their early teens due to heart attack or stoke. Approximately 90% of the HGPS cases are causedby a de novo mutation at 1824 position of the lamin A gene (C1824T, G608G). This mutation does not affect the coded amino acid, but partially activates a cryptic splice donor site in the exon 11, leading to the production of a mutant lamin A mRNA that contains an internal deletion of 150 base pairs. This is then translated into a lamin A mutant protein missing 50 amino acids near the C-terminus, termed “progerin”.
Remarkably, to date, there are over 180 mutations related to the nuclear lamina, and it is associated with at least 14 known human diseases (the laminopathies). However, the molecular mechanisms of lamin A’s function still remain unclear. To investigate this question, my laboratory applies a potent suite of techniques from cell biology, stem cell biology, to genomics. Our goal is two-fold: (1) to develop novel treatments for HGPS; (2) to exploit our knowledge of HGPS to better understand human aging.
Genomics: Mapping Changes in Nuclear Organization
Stem Cell Biology: Studying HGPS Pathogenesis Using Induced Pluripotent Stem Cells (iPSC)
My group is interested in utilizing iPS cells, derived from primary skin fibroblast cells from HGPS patients, as a system to study HGPS pathogenesis in the context of tissue development. Our future studies will address the cellular defects in HGPS-iPS cells and during in vitro differentiation toward various cell lineages. We are particularly interested driving HGPS-iPS cells to vascular smooth muscle cells, endothelial cells, adipocytes, osteoblasts, and keratinocytes, where most severe phenotypes have been observed. The short-term goal of this study is to understand when and where progerin is produced during differentiation, and what are immediate defects caused by progerin at each stage.