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)：本项目的目标是测试早老素(PSS)和PS相互作用蛋白基因的放松调控导致阿尔茨海默病(AD)病理的假设。两个同源早老素基因PS1和PS2的错义突变是家族性早发性阿尔茨海默病(AD)的主要原因。这些基因在最常见的晚期阿尔茨海默病中的作用仍有待阐明。PSS参与蛋白质的降解，如淀粉样前体蛋白(APP)，被认为是导致AD的分子级联机制中的关键因素。AD相关的突变促进了这种切割，而PS1和PS2活性的取消抑制了APP底物的内蛋白分解。因此，可以想象，PSS表达的变化调节了AD的病理。我们的初步数据表明，低氧是PSS和PS相互作用蛋白基因调控的一个重要因素。这些数据有力地表明，PS2在低氧/高氧条件下高度诱导，PS2中调节DNA元件(IRF2/CREBB)的改变增加了启动子区域对与AD相关的应激调节因子的敏感性。我们还鉴定了一个新的早老素同源蛋白家族和高度调控的缺乏功能结构域的早老素亚型。我们假设PSS的活性受1)转录因子的调控，包括自然发生的DNA变异和胁迫调节的DNA元件；2)转录后因子，包括具有显性负效应的PS样蛋白亚型。这项建议的目的是阐明在转录和翻译后水平上调节早老素的分子因素。我们将1)确定与AD有关的新的分子遗传因子(基因单倍型)；2)分离动态调节PSS的新的转录和剪接增强/抑制元件；3)阐明新发现的PS同源蛋白在PS蛋白加工或表达调控中的作用。我们提出了一种融合的方法，它将伴随着AD患者的遗传分析伴随着体外基因变异的系统发育和功能分析。为了实现这些目标，将采用遗传关联分析的方法，定量评估启动子活性的分子分析方法，以及在哺乳动物细胞中进行蛋白质加工的方法，外显子捕获和PS介导的蛋白分解的细胞分析。这些目标的实现将阐明阿尔茨海默病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控阿尔茨海默病主要原因的分子因素，最终有助于开发预防和合理治疗阿尔茨海默病的新策略。