Regulation of Presenilin Genes

早老素基因的调控

• 批准号: 6909933
• 负责人: EVGENY I ROGAEV
• 金额: $ 29.97万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909933
• 关键词: Alzheimer' s disease; gene expression; gene mutation; genetic regulation; genetic regulatory element; genetic susceptibility; human genetic material tag; human subject; neurons; pathologic process; patient oriented research; posttranscriptional RNA processing; presenilin; protein isoforms

DESCRIPTION (provided by applicant): The objective of this project is to test the hypothesis that deregulation of genes for presenilins (PSs) and PS- interacting proteins contributes to Alzheimer's disease (AD) pathology. Missense-mutations in two homologous presenilin genes, PS1 and PS2, are the major cause of familial early onset Alzheimer's disease (AD). The role of these genes in the most common, the late-onsetAD, remains to be elucidated. PSs are involved in the proteolytic cleavage of several proteins, eg., amyloid precursor protein (APP), that is thought to be critical factor in molecular cascade mechanisms leading to AD. AD-associated mutations enhance this cleavage, while the abolishment of PS1 and PS2 activity inhibits the endoproteolysis of APP substrate. It is conceivable, then, that alteration of expression of PSs modulate AD pathology. Our preliminary data suggest hypoxia is an important factor in regulation of genes for PSs and PS- interacting proteins. The data strongly suggest that PS2 is highly inducible by hypoxia/hyperoxia conditions and that alteration of regulatory DNA elements (IRF2/CREBB) in PS2 increases the susceptibility of the promoter region to stress-regulated factors associated with AD. We also identified a novel family of presenilin-homologous proteins and highly regulated presenilin isoforms lacking functional domains. We hypothesize that activity of PSs is modulated by 1) transcriptional factors, including naturally-occurring DNA variations and stress-regulated DNA elements; and 2) post-transcriptional factors, including PS-like protein isoforms with putative dominant negative effects. The goal of this proposal is to elucidate molecular factors that regulate presenilins on transcriptional and posttranslational levels. We will 1) identify novel-molecular-genetic factors (gene haplotypes) contributing to AD; 2) isolate novel transcription and splicing enhancer/repressor elements that dynamically regulate PSs; 3) elucidate the role of newly identified PS-homologous proteins in modulation of processing or expression of PS proteins. We present a convergent approach with which the genetic analysis of AD patients will be accompanied by phylogenic and functional analysis of the gene variations in vitro. To achieve these goals, methods of genetic association analysis, molecular assays for quantitative evaluation of promoter activities, and protein processing in mammalian cells, cellular assays for exon trapping and PS-mediated proteolysis will be undertaken. The accomplishment of these goals will clarify molecular-genetic and epigenetic mechanisms of AD. These studies will contribute to identification of molecular factors regulating the primary causes of AD, and ultimately, to the development of new strategies for prevention and rational therapy of Alzheimer's disease.

描述（由申请人提供）：本项目的目的是检验早老素（PS）和PS相互作用蛋白基因的失调有助于阿尔茨海默病（AD）病理学的假设。早老素基因PS1和PS2的错义突变是家族性早发性阿尔茨海默病（AD）的主要病因。这些基因在最常见的迟发性AD中的作用仍有待阐明。PS参与几种蛋白质的蛋白水解切割，例如，淀粉样前体蛋白（APP），其被认为是导致AD的分子级联机制中的关键因子。AD相关突变增强了这种切割，而PS1和PS2活性的废除抑制APP底物的内蛋白水解。因此，可以想象，PSs表达的改变调节AD病理。我们的初步数据表明，缺氧是一个重要的因素，在调节基因的PS和PS相互作用蛋白。这些数据有力地表明，PS2是高度诱导的缺氧/高氧条件下，在PS2的调节DNA元件（IRF 2/CREBB）的改变增加了易感性的启动子区域与AD相关的应力调节因子。我们还确定了一个新的早老素同源蛋白家族和高度调控的早老素亚型缺乏功能结构域。我们假设PS的活性受1）转录因子，包括天然存在的DNA变异和应激调控的DNA元件;和2）转录后因子，包括具有推定显性负效应的PS样蛋白异构体。本研究的目的是阐明在转录和翻译后水平调控早老素的分子因子。我们将1）确定新的分子遗传因子（基因单倍型）有助于AD; 2）分离新的转录和剪接增强子/阻遏子元件，动态调节PS; 3）阐明新鉴定的PS同源蛋白在调节PS蛋白的加工或表达中的作用。我们提出了一个收敛的方法，AD患者的遗传分析将伴随着体外基因变异的遗传和功能分析。为了实现这些目标，将进行遗传关联分析、用于定量评价启动子活性的分子测定和哺乳动物细胞中的蛋白质加工、用于外显子捕获和PS介导的蛋白质水解的细胞测定的方法。这些目标的实现将有助于阐明AD的分子遗传学和表观遗传学机制。这些研究将有助于确定调节AD主要病因的分子因素，并最终为预防和合理治疗阿尔茨海默病制定新的策略。