Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models

人类和果蝇模型中阿尔茨海默病的功能基因组解剖

• 批准号: 10215922
• 负责人: HUGO J BELLEN
• 金额: $ 162.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10215922
• 关键词: Adult; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Architecture; Atlases; Behavior; Bioinformatics; Biological Assay; Biological Models; Brain; Brain imaging; Candidate Disease Gene; Clinical; Code; Cognition; Communities; Complex; Custom; Data; Disease; Disease susceptibility; Dissection; Drosophila genus; Drosophila melanogaster; Encyclopedia of DNA Elements; Endocytosis; Enhancers; Genes; Genetic study; Genomics; Heterogeneity; Histology; Human; Human Genetics; Individual; Infrastructure; Investigation; Maps; Mediating; Medicine; Modeling; Molecular; Natural Immunity; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Neurosciences; Pathologic; Pathology; Pathway interactions; Phenotype; Pre-Clinical Model; Predisposition; Proteome; Publishing; Research; Resolution; Resources; Robotics; Source; Synapses; System; Tauopathies; Technology; Testing; Therapeutic; Transcend; Transmission Electron Microscopy; United States National Institutes of Health; Untranslated RNA; Validation; Variant; Work; age related; alpha synuclein; cell type; data resource; disorder risk; endophenotype; epigenome; epigenomics; experience; falls; fly; follow-up; functional genomics; gene interaction; genetic analysis; genetic technology; genetic variant; genome resource; genome wide association study; genomic data; high throughput screening; human data; improved; in vivo; innovation; instrumentation; knockout gene; loss of function; motor impairment; neurophysiology; progressive neurodegeneration; protective allele; protective factors; protein TDP-43; proteostasis; rare variant; risk variant; screening; tau Proteins; tool; transcriptome; translation to humans

SUMMARY Alzheimer’s Disease (AD) is projected to affect 13 million people in the US by 2050 and remains neither curable nor preventable. Following remarkable recent progress, the genomic architecture of AD and related dementias (ADRD) is coming into focus. Similar to other common and genetically complex disorders, AD is characterized by substantial locus heterogeneity and polygenic susceptibility: risk or protective alleles are being identified in many distinct genes, and in most individuals, a subset of common and rare variants likely interact to trigger neurodegeneration. The critical next steps include confirmation of the responsible genes, understanding the functional impact of disease-associated variants, elaboration of the relevant cell types and pathways, and determining how polygenic interactions mediate disease risk. We propose an integrated computational and tiered experimental validation strategy to accelerate AD functional genomics, building on advances from the AD Sequencing Project (ADSP) and leveraging powerful technologies available in the fruit fly, Drosophila melanogaster. First (AIM 1), leveraging infrastructure developed for the Clinical Genome Resource and ENCODE projects, we will integrate ADSP results with other human data, including brain transcriptome and epigenome profiles, prioritizing genes and variants for experimental follow-up. Next (AIM 2), using high-throughput Drosophila screening, we will systematically manipulate 2,000 conserved, candidate AD genes in vivo to pinpoint causal modulators of age-dependent neurodegeneration, including interactions with Tau, Aß, and other pathologic triggers. Third (AIM 3), for a subset of 200 prioritized gene candidates, we will generate customized Drosophila strains and characterize cell-type expression and loss-of-function phenotypes. Lastly (AIM 4), for 50 high-priority targets, we will experimentally probe mechanisms in-depth, including testing of cell-type specific requirements (neurons vs. glia) and examining gene-gene interactions that define relevant pathways. We will broadly share all project data and resources with the research community (AIM 5). Our integrative, tiered, cross-species strategy promises rapid functional annotation of ADSP targets using powerful, in vivo assays in the aging nervous system of Drosophila, and is ideally suited for reciprocal cross-validation in complementary mammalian preclinical models. On a scale and timeframe not currently possible in other model systems, our innovative experimental strategy will transcend barriers to translation of human genetic discoveries and catalyze breakthroughs in our understanding AD pathobiology.

概括 阿尔茨海默氏病（AD）预计到2050年将影响美国1300万人，并且既不是 可以治愈也可以预防。随着最近的显着进展，AD和相关的基因组架构 痴呆症（ADRD）开始焦点。与其他常见且普遍复杂的疾病相似，AD是 具有实质基因座异质性和多基因敏感性的特征：风险或保护等位基因是 在许多不同的基因中被鉴定出来，在大多数个体中，一部分常见和稀有变体可能 相互作用以触发神经变性。关键的下一步包括确认负责基因， 了解与疾病相关变体的功能影响，相关细胞类型的阐述以及 途径，并确定多基因相互作用如何介导疾病的风险。我们提出了一个综合的 基于AD功能基因组学的计算和分层实验验证策略，以 广告测序项目（ADSP）的进步和利用水果中可用的强大技术 飞，果蝇果蝇。首先（AIM 1），为临床基因组开发的利用基础设施 资源和编码项目，我们将将ADSP结果与其他人类数据（包括大脑）集成 转录组和表观基因组谱，优先考虑基因和用于实验随访的变体。下一个（AIM 2）， 使用高通量果蝇筛选，我们将系统地操纵2,000个保守的候选AD 体内基因以查明依赖年龄依赖性神经变性的因果调节剂，包括与 tau，aß和其他病理触发因素。第三（AIM 3），对于200个优先基因候选者的子集，我们将 产生定制的果蝇菌株，并表征细胞类型的表达和功能丧失表型。 最后（AIM 4），对于50个高优先级目标，我们将深入实验探测机制，包括测试 细胞类型的特异性要求（神经元与神经胶质）和研究定义相关性的基因 - 基因相互作用 途径。我们将与研究界广泛共享所有项目数据和资源（AIM 5）。我们的 综合，分层的跨物种策略有望使用强大的， 果蝇衰老神经系统中的体内刺激性，非常适合互惠交叉验证 完全哺乳动物的临床前模型。在其他模型中，目前无法进行规模和时间表 系统，我们的创新实验策略将超越人类通用翻译的障碍 在我们的理解AD病理生物学中，发现并促进了突破。