Cellular Mechanisms in Hutchinson-Gilford Progeria Syndrome and Normal Aging

哈钦森-吉尔福德早衰综合症和正常衰老的细胞机制

基本信息

批准号：
8144266
负责人：
KAN CAO
金额：
$ 29.75万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144266
关键词：
5&apos Splice Site Address Affect Age Age-Years Aging Aging-Related Process Alopecia Amino Acids Aneuploidy Applications Grants Base Pairing Biochemical Biological Birth Bulla C-terminal Cardiovascular Diseases Cell Nucleus Cells Cessation of life Child Chromatin Chromatin Structure Chromatin Structure Alteration Chromosomes Clinical Treatment Code Coupled Couples DNA DNA Sequence Data Defect Epigenetic Process Essential Genes Exons Fatty acid glycerol esters Fibroblasts Future Gene Expression Genes Growth Hereditary Disease Heterochromatin Immunoprecipitation Instruction Interphase Lamin Type A Lead Maps Messenger RNA Methods Microarray Analysis Mitotic Modeling Modification Molecular Mutation Myocardial Infarction Normal Cell Nuclear Nuclear Lamina Nuclear Pore Nucleotides Osteoporosis Pathway interactions Patients Peripheral Phenotype Point Mutation Positioning Attribute Premature aging syndrome Process Production Progeria Proteins RNA Splicing Reporting Research Resolution Role Site Skin Stroke Syndrome Technology Testing Translating bone chromatin immunoprecipitation cost genome-wide high throughput analysis improved lamin C mutant next generation normal aging prelamin A premature research study senescence skeletal abnormality subcutaneous

项目摘要

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.

哈钦森-吉尔福德早衰综合症 (HOPS) 是一种罕见的遗传性疾病，其特征是急剧的过早衰老。 HGPS 患者出生时表现正常，但开始出现脱发、生长一岁时出现发育迟缓、骨骼异常、骨质疏松症和皮肤硬皮病。平均而言， 12 岁时死于心脏病或中风。经典 HGPS 是由从头点引起的 LMNA 基因的外显子 11（1824，C->T）发生突变，激活隐秘剪接供体并导致突变核纤层蛋白一种称为“progerin”的蛋白质，缺乏正常的切割位点以去除 C 端法尼基团体。我的长期研究目标是揭示 HGPS 和正常情况下的细胞机制老化。在具体目标1中，我们建议分析早老素引起的缺陷并鉴定早老素互动的伙伴。将采取组合的细胞生物学和生化方法来实现这一目标目的。在具体目标 2 中，我们将研究早老素在正常衰老过程中的作用。我们建议早老素在正常细胞中产生，并且与那些细胞的衰老有因果关系。表达它。为了验证这个想法，我们将研究正常细胞中如何产生早老素，以及早老素与正常衰老之间的功能关系。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将染色质免疫沉淀与新一代测序 (ChlP-seq) 相结合的方法以及基因表达分析。来自这些高通量分析的数据将提供有价值的有关 HGPS 细胞中染色质结构何时以及如何发生变化的信息，以及哪些重要信息 HGPS 细胞中的基因/通路受到影响。