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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：
10681445
负责人：
HUGO J BELLEN
金额：
$ 159.5万
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/10681445
关键词：
Acceleration Adult Affect Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Architecture Atlases Behavior Bioinformatics Biological Assay Biological Models Brain Brain imaging Candidate Disease Gene Clinical Code Cognition Collaborations Communities Complex Data Disease Disease susceptibility Dissection Drosophila genus Drosophila melanogaster Encyclopedia of DNA Elements Endocytosis Enhancers Genes Genetic study Genomics Heterogeneity Histology Homologous Gene Human Human Genetics Individual Infrastructure Investigation Maps Mediating Medicine Modeling Molecular Natural Immunity Nerve Degeneration Nervous System Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neurons Neurosciences Pathologic Pathology Pathway interactions Persons Phenotype Pre-Clinical Model Predisposition Proteome Publishing Research Resolution Resources Robotics Source Structure 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 disorder risk endophenotype epigenome epigenomics experience falls fly follow-up functional genomics gene conservation 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 model organism 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 translational barrier

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.

总结