Current Research
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 between HGPS and normal aging. Children with HGPS die at their early teens due to heart attack or stoke. Approximately 90% of the HGPS cases are caused by 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”.
Lamin A is a component of the nuclear lamina. Years of research have revealed that the lamina not only plays a major role in the maintenance of nuclear structure, but also regulates gene transcription, nuclear pore positioning, and chromatin organization.
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
It is known that lamin A interacts with a variety of nuclear factors, including transcriptional regulators, chromatin, and nuclear membrane associated proteins. However it still remains unclear which proteins, genes, or regulatory DNA elements interact with lamin A in normal cells,or with progerin and lamin A in HGPS cells. We hypothesize that perturbations of chromatin structure and nuclear organization by progerin result in genome-wide defects in gene transcription, ultimately leading to HGPS. To test this idea, our approach combines chromatin immunoprecipitation, Hi-C approach of mapping of high-order nuclear organization, with next-generation sequencing and/or mass spectrometry techniques. Our goal is to identify differentially modified chromatin regions and differentially associated protein/DNA elements with lamin A and progerin in HGPS cells. Combined with gene expression analysis, we also aim to develop novel methods to integrate those multi-dimensional genomic data with gene expression profiles, and to identify key players in HGPS pathogenesis.
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.
Normal Aging Connection
One of the most important biological questions in HGPS study is whether HGPS, a premature aging model, can be used to understand the normal aging process. To address this question, we have shown the existence of progerin mRNA and protein in normal skin fibroblasts. My laboratory would like to further examine the causative relationship between progerin production and the aging process, to study the regulation of progerin production in normal cells, and to determine the contribution of progerin in normal human aging.