Biochem. Characterization of Hutchinson-Gilford Progeria Syndrome

描述（由申请人提供）：哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的遗传疾病，其特征是过早衰老。受影响的儿童在出生时表现正常，但在一年内发展出老年的特征。大多数HGPS儿童在平均13岁时死于心脏病。遗传学研究在18例典型HGPS病例中发现了层状蛋白a /C （LMNA）基因突变。该突变导致产生具有内部缺失的突变的层粘连蛋白a。突变的HGPS纤层蛋白A导致加速衰老的机制尚不清楚。核纤层蛋白A似乎是通过与其他细胞因子的一组特异性蛋白相互作用来维持细胞核结构和功能的。因此，我假设突变HGPS纤层蛋白a的表达导致早衰，这是核内含有纤层蛋白a复合物的组成和功能改变的结果。为了验证这一假设，在目标1中，我将首先定义HGPS成纤维细胞的细胞生长特性，以确定导致这些细胞在培养中寿命有限的细胞途径。然后在目标2中，我将采用生化方法来鉴定和表征与野生型和突变型HGPS层粘胶蛋白A相关的蛋白质。

DESCRIPTION (provided by applicant): Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature senescence. Affected children appear normal at birth, but within a year develop characteristic features of old age. The majority of HGPS children die from cardiac disease at an average age of 13 years. Genetic studies have identified a mutation in the lamin A/C (LMNA) gene in 18 classical HGPS cases. The mutation results in the production of a mutant lamin A protein with an internal deletion. The mechanism by which the mutated HGPS lamin A protein leads to accelerated aging is unknown. Lamin A appear to maintain nuclear structure and function through a set of specific protein interaction with other cellular factors. I therefore hypothesize that expression of the mutant HGPS lamin-A protein results in premature aging as a consequence of the altered composition and function of lamin A-containing complexes within the nucleus. To test this hypothesis, in Aim 1 I will first define the cellular growth properties of HGPS fibroblast to identify the cellular pathways responsible for the limited life span of these cells in culture. Then in aim 2, I will employ biochemical approaches to identify and characterize the proteins associated with wild type and mutant HGPS lamin A.