Biochem. Characterization of Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford早老综合征（HGPS）是一种罕见的遗传性疾病，其特征在于过早衰老， 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人的特征。 年龄大多数HGPS儿童死于心脏病，平均年龄为13岁。遗传研究 在18例典型HGPS病例中发现了核纤层蛋白A/C（LMNA）基因突变。所述突变导致 产生具有内部缺失的突变核纤层蛋白A蛋白。变异的基因 HGPS核纤层蛋白A蛋白导致加速老化是未知的。核纤层蛋白A似乎保持核结构 并通过一组与其他细胞因子的特异性蛋白质相互作用发挥作用。因此我假设 突变型HGPS层蛋白-A蛋白的表达导致作为结果的过早衰老。 改变核内含有核纤层蛋白A的复合物的组成和功能。为了验证这个假设， 在目的1中，我将首先定义HGPS成纤维细胞的细胞生长特性，以确定细胞途径 导致这些细胞在培养中的寿命有限。那么在目标2中，我将使用生化武器 鉴定和表征与野生型和突变型HGPS层粘连蛋白A相关的蛋白质的方法。

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 2,1 will employ biochemical approaches to identify and characterize the proteins associated with wild type and mutant HGPS laminA.