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：
8320210
负责人：
KAN CAO
金额：
$ 28.53万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320210
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 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 base 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 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.

Hutchinson-Gilford Progeria综合征（HOPS）是一种罕见的遗传疾病，其特征是戏剧性的过早衰老。出生时HGP的患者看起来正常，但开始显示脱发，生长迟钝，骨异常，骨质疏松和硬皮皮肤降至一岁。平均死亡发生在12岁时因心脏病发作或中风而发生。经典的HGP是由从头开始引起的 LMNA基因的外显子11（1824，c-> t）中的突变，激活一个隐秘的剪接供体并导致A 突变层粘连蛋白A缺乏正常裂解位点的蛋白质以去除C末端Farnesyl 团体。我的长期研究目标是发现HGP和正常的细胞机制老化。在特定的目标1中，我们建议分析孕激素引起的缺陷并鉴定孕激素互动合作伙伴。将采取一种同时的细胞生物学和生化方法来实现这一目标目的。在特定的目标2中，我们将研究过程在正常衰老过程中的作用。我们提出了这一点雌激素是在正常细胞中产生的，并且与那些细胞的衰老有关表达它。为了测试这一想法，我们将研究正常细胞中如何产生孕激素，并如何 JSrogerin与正常衰老之间的功能关系。在特定目标3中，我们建议产生高分辨率， HGPS细胞中染色质结构和基因表达改变的全基因组图使用一种将染色质免疫沉淀与下一代测序（CHLP-SEQ）伴侣的方法以及基因表达分析。这些高通量分析的数据将提供有价值的有关HGPS细胞中染色质结构的变化何时以及如何发生的信息，以及哪些必不可少的基因/途径在HGPS细胞中受到影响。