Biochem. Characterization of Hutchinson-Gilford Progeria Syndrome

描述（由申请人提供）：Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的遗传性疾病，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儿童死于心脏病，平均年龄为13岁。 遗传学研究已经在18个典型的HGPS病例中发现了核纤层蛋白A/C（LMNA）基因的突变。 突变导致产生具有内部缺失的突变核纤层蛋白A蛋白。 突变的HGPS核纤层蛋白A蛋白导致加速老化的机制尚不清楚。 核纤层蛋白A似乎通过与其他细胞因子的一系列特异性蛋白质相互作用来维持核结构和功能。 因此，我假设突变HGPS层粘连蛋白-A蛋白的表达导致细胞核内的层粘连蛋白A复合物的组成和功能改变，从而导致过早衰老。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，以确定负责这些细胞在培养中的有限寿命的细胞途径。 然后在目标2中，我将采用生物化学方法鉴定和表征与野生型和突变型HGPS核纤层蛋白A相关的蛋白。

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.