A systems biology approach in Drosophila to identify novel factors that influence AD pathogenicity

果蝇系统生物学方法识别影响 AD 致病性的新因素

• 批准号: 9413012
• 负责人: Daniel Edward Promislow
• 金额: $ 335.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9413012
• 关键词: Affect; Age; Aging; Alleles; Alpha Cell; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Behavior; Behavioral; Binding; Biochemical; Biochemical Pathway; Bioenergetics; Biological Markers; Biology; Brain; Cells; Complex; Data; Disease; Disease Resistance; Drosophila genome; Drosophila genus; Drosophila melanogaster; Early Onset Familial Alzheimer' s Disease; Elderly; Electrophysiology (science); Elements; Exhibits; Eye; Foundations; Gait; Genes; Genetic; Genetic Epistasis; Genetic Models; Genetic Structures; Genetic Variation; Genotype; Goals; Human; Individual; Late Onset Alzheimer Disease; Lead; Link; Maps; Measurement; Measures; Mediating; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Persons; Phenotype; Physiologic pulse; Physiological; Play; Population; Protein Biochemistry; Protein Dynamics; Proteins; Publishing; Research Personnel; Resistance; Risk; Risk Factors; Role; Severities; Specificity; Stress; Structure; System; Systems Biology; Tauopathies; Technology; Testing; Therapeutic Intervention; Toxic effect; Translating; Variant; Vision; Walking; Work; abeta accumulation; age related; age related neurodegeneration; brain cell; cell type; diagnostic biomarker; fly; gene environment interaction; genome wide association study; genome-wide; in vivo; insight; kinematics; metabolomics; mitochondrial dysfunction; molecular scale; mortality; neurodegenerative phenotype; novel; predictive marker; reference genome; skills; tau Proteins; tau expression; trafficking; trait; transcriptomics

Alzheimer's disease (AD) is a common neurodegenerative disorder affecting more than 10% of the population over age 65, and almost 50% of those over age 85. Early onset familial AD is typically caused by mutations in one of just three autosomal genes. In contrast, the more common, late-onset sporadic AD (LOAD), which is associated with amyloid β accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, appears to be influenced by a very large number of genes, most of which are unidentified. Genome-wide association studies of LOAD point to genome-wide epistasis and gene-×-environment interactions contributing to overall risk. Both the genetic basis and the downstream effects of AD are system-wide and complex. To parse this complexity in both causes and consequences of AD, here we create a novel Systems Biology Pipeline and apply it to a powerful genetic model of AD using the fruit fly, Drosophila melanogaster. With three complementary aims, our pipeline enables us to create a comprehensive genotype-phenotype map of AD. Our first aim uses the fully sequenced Drosophila Genetic Reference Panel (DGRP) to identify fly strains that amplify or ameliorate the effects of Aβ and tau on age-related neurodegeneration, and characterizes the metabolomic and single-cell brain transcriptomic networks associated with this amplification and protection. The second aim develops the fly as a powerful model for downstream systems-wide phenotypes, from electrophysiological measures of specific single cell types in the brain, to machine-vision analysis of walking gait dynamics. To help us understand how upstream variation in genes and molecular networks (Aim 1) translates to downstream cellular and behavioral phenotypes (Aim 2), Aim 3 examines the protein dynamics of Aβ and tau, including their turnover, aggregation and abundance, and the influence of Aβ and tau on mitochondrial integrity, including mitochondrial morphology, trafficking and turnover. Aim 3 will then compare these elements in strains that are most sensitive to the deleterious effects of Aβ and tau with those that are most resistant, delineating molecular and cellular mechanisms that influence Aβ and tau toxicity. To accomplish these aims, we have constructed an outstanding team of researchers with highly complementary skills. Our published and preliminary data presented here establish our ability to measure genotypic variation in AD risk in Drosophila and construct and analyze large-scale molecular networks associated with that risk, to study the phenotypic consequences of AD from electrical pulses in a single neuron to intricate behaviors in a whole fly, and to discover the underlying biochemical mechanisms that link genotype to phenotype. Previous work with Drosophila has played an important role in our understanding of both basic biology and of disease mechanism, including neurodegenerative diseases. The studies proposed here have the potential to shed new insight on the complex, interacting pathways that influence AD pathogenesis in natural populations, potentially leading to new biomarkers and new opportunities for therapeutic intervention in AD.

阿尔茨海默病（AD）是一种常见的神经退行性疾病，影响超过10%的人口