Modifiers of beta-amyloid metabolism and deposition

β-淀粉样蛋白代谢和沉积的调节剂

基本信息

批准号：
8092683
负责人：
Bruce T Lamb
金额：
$ 30.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092683
关键词：
Accounting Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Applications Grants Biological Models Brain Candidate Disease Gene Cause of Death Cessation of life Characteristics Cholesterol Chromosomes Complex Congenic Mice Congenic Strain Consomic Strain Dementia Deposition Development Diagnosis Diagnostic Diet Disease Elderly Environment Environmental Exposure Environmental Risk Factor Epidemiologic Studies Epidemiology Etiology Exhibits Fatty acid glycerol esters Funding Gene Expression Microarray Analysis Generations Genes Genetic Genetic Heterogeneity Genetic Risk Goals Health Human Human Genetics Inbred Strains Mice Inbreeding Individual Investigation Late Onset Alzheimer Disease Longevity Metabolism Modeling Mouse Strains Mus Mutation Nerve Degeneration Neurodegenerative Disorders Partner in relationship Pattern Peptide Fragments Peptides Phenotype Presenile Alzheimer Dementia Production Proteins Risk Factors Role Senile Plaques Therapeutic Intervention Transgenes Transgenic Mice abeta accumulation age related amyloid precursor protein processing behavioral impairment disability disease phenotype dosage extracellular genetic resource genetic variant insight knockout gene mouse model neuropathology overexpression presenilin-1 presenilin-2

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common dementing disorder of late life, is a major cause of disability and death in the elderly. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ¿-amyloid (A¿) peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous proposed genetic and environmental etiologies. Human genetic studies have shown that altered dosage and mutations in the amyloid precursor protein gene as well as mutations in presenilin 1 and presenilin 2 genes all cause early-onset AD, while the APOE gene is major risk factor in late-onset AD. Considerable evidence suggests that these genetic factors alter A¿ metabolism and/or A¿ deposition. However, the AD genes identified thus far account for less than 30% of genetic risk for AD. Due to the inherent variability and genetic heterogeneity in late-onset neurodegenerative disorders, the identification of the remainder of the genetic and environmental factors that modulate AD risk have proven extremely difficult. Over the past decade and a half, several groups, including our own, have focused on the development of accurate and defined mouse models of AD, in which both the genetic background and environmental exposure can be precisely and reproducibly modified in an effort to gain insight into factors that modify APP processing, the production and deposition of A¿ peptides, the onset of dementia and the neuropathological abnormalities that occur in AD. In the previous funding period of this grant application, we generated congenic strains, in which a human AD transgene was transferred into different inbred mouse strains. We subsequently characterized the effects of different inbred genetic backgrounds and specific genetic alterations on A¿ metabolism and deposition and other AD phenotypes and identified unique mouse genetic loci that regulate metabolism and deposition. In addition, in preliminary studies we determined that the effects of an environmental factor, namely high-fat/high-cholesterol diets, on brain A¿ levels are dependent upon the genetic background of the mice. The current studies seek to expand and extend these studies with a focus on genetic and environmental factors that regulate A¿ metabolism and deposition in two inbred mouse strains with the most divergent A¿ phenotypes, C57BL/6J and A/J, using the unique genetic resources available for these strains. The specific aims of the current proposal are to: 1) Identify mouse chromosomes with gene(s) that regulate A¿ metabolism and deposition. 2) Identify and characterize genetic loci that regulate A¿ deposition. 3) Characterize genetic loci responsible for diet-induced alterations in A¿ metabolism and deposition. PUBLIC HEALTH RELEVANCE: Human genetic studies have demonstrated that accumulation and aggregation of small peptide fragments, termed beta-amyloid, is central to the disease mechanisms underlying Alzheimer's disease, a major cause of death and disability in the elderly. However, it remains unclear how the multitude of postulated genetic and environmental risk factors for human AD directly influence the production and aggregation of beta-amyloid. The current studies seek to identify and characterize additional genetic and environmental (namely high-fat/high-cholesterol diets) factors influence beta-amyloid generation and deposition within the brains of transgenic mouse models of AD.

描述（由适用提供）：阿尔茨海默氏病（AD）是后期生活中最常见的痴呆症，是最古老的混乱和死亡的主要原因。 AD的特征和诊断为独特的神经病理学改变，包括 - 淀粉样蛋白（a¿）肽的细胞外沉积物。流行病学研究表明，AD是一种复杂的，与年龄有关的疾病，具有许多拟议的遗传和环境病因。人类遗传研究表明，淀粉样蛋白前体蛋白基因的剂量和突变改变，以及presenilin 1和Presenilin 2基因的突变均引起早发AD，而APOE基因是晚期癌症的主要危险因素。大量证据表明，这些遗传因素改变了代谢和/或沉积。但是，迄今为止确定的AD基因占AD遗传风险的30％。由于晚期神经退行性疾病的遗传性和遗传异质性，因此证明调节AD风险的其余遗传和环境因素的鉴定已被证明非常困难。在过去的十年半中，包括我们自己的几个小组都集中在准确和定义的AD模型上，其中遗传背景和环境暴露都可以精确而可重复地修改，以深入了解修改应用程序处理的因素，以修改应用程序处理，肽的生产和沉积物，并发生了痴呆症和神经学的发作。在本赠款应用的前几个资金期间，我们产生了先天性菌株，其中人类AD变换被转移到不同的近交小鼠菌株中。随后，我们表征了不同的近交遗传背景以及特定遗传改变对A的代谢和沉积以及其他AD表型的影响，并确定了调节代谢和沉积的独特小鼠遗传基因座。此外，在初步研究中，我们确定环境因素（即高脂/高胆固醇饮食）对大脑A水平的影响取决于小鼠的遗传背景。当前的研究旨在扩展和扩展这些研究，重点是在两种近交小鼠菌株中调节A代谢和沉积的遗传和环境因素，其中最有不同的表型，C57BL/6J和A/J，使用这些菌株可用的独特遗传资源。当前建议的具体目的是：1）用调节A型代谢和沉积的基因鉴定小鼠染色体。 2）识别并表征调节沉积物的遗传基因座。 3）表征负责饮食引起的代谢和沉积改变的遗传位置。公共卫生相关性：人类遗传学研究表明，称为β-淀粉样蛋白的小胡椒片段的积累和聚集是阿尔茨海默氏病的疾病机制的核心，这是老年人死亡和残疾的主要原因。但是，尚不清楚人类AD的众多遗传和环境风险因素如何直接影响β-淀粉样蛋白的产生和聚集。当前的研究旨在识别和表征其他遗传和环境（即高脂/高胆固醇饮食）的因素影响AD的转基因小鼠模型的大脑内的β-淀粉样蛋白产生和沉积。