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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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.

概括预计到 2050 年，阿尔茨海默病 (AD) 将影响美国 1,300 万人，而且目前这种疾病仍然存在随着最近取得的显着进展，AD 及相关疾病的基因组结构变得不可治愈或可预防。与其他常见且复杂的遗传性疾病类似，痴呆症 (ADRD) 正在成为人们关注的焦点。以显着的基因座异质性和多基因易感性为特征：风险或保护性等位基因是在许多不同的基因中被识别，并且在大多数个体中，可能存在常见和罕见变异的子集相互作用以引发神经变性，接下来的关键步骤包括确认相关基因，了解疾病相关变异的功能影响、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风险。加速 AD 功能基因组学的计算和分层实验验证策略 AD 测序项目 (ADSP) 的进步并利用水果中可用的强大技术首先，果蝇 (AIM 1)，利用为临床基因组开发的基础设施。 Resource 和 ENCODE 项目，我们将把 ADSP 结果与其他人类数据集成，包括大脑转录组和表观基因组图谱，确定后续实验的基因和变异的优先顺序 (AIM 2)，通过高通量果蝇筛选，我们将系统地操作 2,000 个保守的候选 AD 体内基因以查明年龄依赖性神经变性的因果调节剂，包括与第三，对于 200 个优先候选基因的子集，我们将 Tau、Aß 和其他病理触发因素。生成定制的果蝇菌株并表征细胞类型表达和功能丧失表型。最后（AIM 4），对于50个高优先级目标，我们将通过实验深入探索机制，包括测试细胞类型特定要求（神经元与神经胶质细胞）并检查定义相关的基因-基因相互作用我们将与研究界广泛共享所有项目数据和资源（AIM 5）。综合、分层、跨物种策略有望使用强大的、果蝇衰老神经系统的体内测定，非常适合以下领域的相互交叉验证互补的哺乳动物临床前模型的规模和时间范围目前在其他模型中是不可能的。系统，我们的创新实验策略将超越人类基因翻译的障碍发现并促进我们对 AD 病理学理解的突破。