Biochem. Characterization of Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford早衰症(HGPS)是一种罕见的遗传性疾病，其特征是早产 衰老。受影响的儿童在出生时看起来是正常的，但在一年内就会出现老年人的特征 年龄。大多数HGPS儿童死于心脏病的平均年龄为13岁。遗传学研究 在18例典型HGPS病例中发现了层蛋白A/C(LMNA)基因突变。这种突变会导致 产生具有内部缺失的突变层粘连蛋白A蛋白。基因突变的机制 HGPS层蛋白A蛋白导致衰老加速尚不清楚。拉米素A似乎维持了核结构 并通过一系列特定的蛋白质与其他细胞因子相互作用而发挥作用。因此我假设 突变的HGPS lamin-A蛋白的表达会导致过早衰老。 核内含层蛋白A的复合体的组成和功能发生改变。为了检验这一假设， 在目标1中，我将首先定义HGPS成纤维细胞的细胞生长特性，以确定细胞通路 对这些细胞在培养过程中有限的寿命负责。然后在目标2，1中将使用生化 鉴定和鉴定与野生型和突变型HGPS叶片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.