Systems Modeling of Alzheimers Disease in C. elegans

线虫阿尔茨海默病的系统建模

• 批准号: 9414234
• 负责人: Coleen Tara Murphy
• 金额: $ 234.4万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414234
• 关键词: Age; Aging; Aging-Related Process; Alpha Cell; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Animal Model; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Cell model; Cells; Chemotaxis; Chronic Disease; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Common Core; Computer Analysis; Computer Simulation; Computing Methodologies; Cost of Illness; Data; Data Set; Dementia; Disease; Enhancers; Environmental Risk Factor; Etiology; Exhibits; Functional disorder; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic screening method; Genetic study; Genome; Health; Human; Human Genetics; Human Genome; Impaired cognition; Intervention; Learning; Longevity; Memory; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurons; Nucleic Acid Regulatory Sequences; Output; Pathogenesis; Pathogenicity; Pathologic Processes; Pathway interactions; Patient Care; Patients; Pharmacologic Substance; Play; Population; Predisposition; Prevention; Preventive treatment; Process; RNA Interference; Regulation; Regulator Genes; Research; Resources; Risk Factors; Role; Senile Plaques; Short-Term Memory; Signal Transduction; Site; Statistical Models; Symptoms; System; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Treatment Efficacy; Untranslated RNA; Variant; age related; cell motility; cerebral atrophy; clinically relevant; cognitive function; cost; curative treatments; disease phenotype; experimental analysis; extracellular; genetic approach; genetic variant; genome wide association study; genomic data; knock-down; long term memory; nervous system disorder; neuron loss; neuropathology; new therapeutic target; novel strategies; programs; risk variant; tau Proteins; therapeutic candidate; therapeutic development; therapeutic target; tool

PROJECT SUMMARY Alzheimer’s Disease (AD) is a major aging-related neurological disorder that afflicts roughly 5.3 million Americans, with total US annual costs of ~ $226 billion. Despite intensive efforts to characterize the regulation of pathological processes of AD, particularly the generation of -amyloid plaques, current interventions aimed at blocking -amyloid aggregation have only modest effects on clinical symptoms, suggesting that new approaches to find risk factors independent of -amyloid aggregation should be investigated, particularly to identify proximal causes of the disease. Genetic studies in model organisms have demonstrated that evolutionarily conserved pathways modulate aging, and interventions that target these pathways can dramatically extend mammalian healthspan and lifespan. C. elegans has been at the forefront of model organism longevity studies, revealing new genes, pathways, and molecular mechanisms that regulate the rate of aging and age-related declines, including cognitive decline. In parallel, Genome-wide association (GWAS) studies have implicated a role for gene regulatory changes as a risk factor for AD. AD risk variants in gene regulatory regions may dysregulate context-specific transcriptional outputs, contributing to susceptibility to AD independent of the regulation and generation of -amyloid plaques. Our hypothesis is that by defining a cell’s gene regulatory networks during aging and in genetically predisposed AD neuropathological states, it will be possible to both infer the environmental signals the cell receives and explain its resulting program of gene expression. These age- dependent transcriptional changes may be conserved in neurons across evolutionary time scales, and may contribute to cognitive decline in the model system C. elegans, as well. We will leverage the strengths of this model system (simple genetics, short lifespan, rapid aging, functional assays of learning and memory, and transcriptional analysis of isolated neurons), combined with data from genomic and genetic studies of AD and experimental results from human neuronal cells, to identify shared gene regulatory networks that may contribute to the susceptibility to AD. These genes and gene networks will provide important new targets for pharmaceutical interventions for the onset and progression of Alzheimer’s Disease.

项目概要 阿尔茨海默病 (AD) 是一种与衰老相关的主要神经系统疾病，大约有 530 万人患有这种疾病 美国人，美国每年的总成本约为 2260 亿美元。尽管付出了巨大的努力来描述监管的特征 AD 的病理过程，特别是 β-淀粉样斑块的产生，目前的干预措施旨在 阻断 -淀粉样蛋白聚集对临床症状只有适度的影响，这表明新方法 应研究寻找独立于 -淀粉样蛋白聚集的危险因素，特别是确定近端淀粉样蛋白聚集的风险因素。 疾病的原因。模式生物的遗传研究表明，进化上保守的 途径调节衰老，针对这些途径的干预措施可以显着延长哺乳动物的寿命 健康寿命和寿命。线虫一直处于模式生物长寿研究的前沿，揭示了 调节衰老速度和与年龄相关的衰退的新基因、途径和分子机制， 包括认知能力下降。与此同时，全基因组关联（GWAS）研究表明 基因调控变化是 AD 的危险因素。基因调控区域的 AD 风险变异可能失调 上下文特定的转录输出，导致对 AD 的易感性，与调节无关 -淀粉样斑块的产生。我们的假设是，通过定义细胞的基因调控网络 衰老和具有遗传倾向的 AD 神经病理状态，都可以推断 细胞接收环境信号并解释其产生的基因表达程序。这些年龄—— 依赖的转录变化可能在整个进化时间尺度的神经元中保守，并且可能 也会导致模型系统线虫的认知能力下降。我们将充分发挥这一优势 模型系统（简单的遗传学、短寿命、快速衰老、学习和记忆的功能分析，以及 分离神经元的转录分析），结合 AD 和 AD 的基因组和遗传学研究的数据 来自人类神经元细胞的实验结果，以确定可能有助于的共享基因调控网络 AD 的易感性。这些基因和基因网络将为制药提供重要的新靶标 对阿尔茨海默病的发病和进展进行干预。