Cellular Mechanisms in Hutchinson-Gilford Progeria Syndrome and Normal Aging

Hutchinson-Gilford早衰症(Hop)是一种罕见的遗传性疾病，其特征是戏剧性的 过早衰老。HGPS患者出生时看起来正常，但开始显示脱发、生长 发育迟缓、骨骼异常、骨质疏松症和一岁以下皮肤硬皮病。平均而言， 12岁时死于心脏病发作或中风。经典的HGPS是由一个新的点引起的 LMNA基因外显子11(1824，C-GT；T)突变，激活一个隐蔽的剪接供体，导致 突变层粘连蛋白：一种被称为“孕蛋白”的蛋白质，它缺少去除C-末端法尼基的正常切割位点 一群人。我的长期研究目标是揭示HGPS和Normal的细胞机制 衰老。在特定的目标1中，我们建议分析孕激素引起的缺陷并识别孕激素 互动伙伴。我们将采用细胞生物学和生物化学相结合的方法来实现这一目标。 瞄准。在特定的目标2中，我们将研究孕激素在正常衰老过程中的作用。我们建议 孕激素是在正常细胞中产生的，与下列细胞的衰老有关 把它表达出来。为了测试这一观点，我们将研究正常细胞中孕激素是如何产生的，以及 孕激素与正常衰老的功能关系。在具体目标3中，我们建议生成高分辨率， HGPS细胞染色质结构和基因表达变化的全基因组图谱 使用一种将染色质免疫沉淀与下一代测序(ChLP-SEQ)相结合的方法 以及基因表达分析。这些高吞吐量分析的数据将提供有价值的 关于HGPS细胞染色质结构何时和如何发生变化的信息，以及哪种必要的 基因/通路在HGPS细胞中受到影响。

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 combined 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 progerin and normal aging. In specific aim 3, we propose to generate high-resolution, 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.