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Project 2: Role of Retrotransposable Element Activity in Drosophila Models of Alzheimer's Disease

项目2：逆转录转座元件活性在阿尔茨海默病果蝇模型中的作用

基本信息

批准号：
10581529
负责人：
STEPHEN L HELFAND
金额：
$ 57.05万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581529
关键词：
ATAC-seq Acceleration Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Bioinformatics Biological Models Brain Cells Chromatin Collaborations Consumption Development Disease Disease Progression Drosophila genus Elements Functional disorder Genes Genetic Genetic Screening Genetic Transcription Goals Heterochromatin Homeostasis Homologous Gene Human Inflammation Intervention Life Extension Longevity Maintenance Mammals Methods Modeling Molecular Mus Mutagenesis Nerve Degeneration Nervous System Neuroglia Neurons Organism Pathway interactions Phenotype Physiological Process Proteins Regulation Reporter Retrotransposon Role Series Somatic Cell Testing Time Tissues Work age effect age related brain cell cell type epigenome fly gene repression gene therapy innovation normal aging novel remediation single cell analysis single-cell RNA sequencing tissue culture tool

项目摘要

The overall goals of this proposal are to exploit the Drosophila model system to determine the role of retrotransposable elements (RTEs) in the progression of cellular dysfunction that occurs during aging and disease, and to develop interventions that suppress RTE activity to extend healthy life span and delay the onset and progression of diseases such as Alzheimer's Disease (AD). We hypothesize that increased activity of RTEs with age leads to loss of cellular and organismal homeostasis in somatic cells promoting aging. This in turn interacts with AD-related changes in chromatin and RTE activity to accelerate neurodegeneration. We will use the powerful molecular and genetic tools, as well as the short life span of Drosophila, to determine how aging and human AD-related proteins affect the activity of RTEs and chromatin state in the brain and identify new and novel genes that repress RTE activity and AD-related phenotypes in order to extend healthy life span and delay the onset and progression of fly AD. We will examine how aging affects the activity of RTEs in specific subsets of neurons and glia, and in turn, how this affects both normal aging processes and neurodegeneration in fly AD models. Using the Drosophila model, we will employ mutagenesis screens to rapidly identify new genes and physiological pathways controlling RTE activity and use these genetic interventions to perform detailed phenotypic analyses over the entire life span of the organism, something that would not be possible in humans, and would be prohibitively expensive and time-consuming to do in mammalian models on any large scale. The aims of this proposal are to test the hypotheses that aging and AD interact to (i) increase RTE activity and (ii) alter chromatin and the epigenome in selective cells in the adult fly brain; and (iii) use forward genetic screens in Drosophila to isolate new suppressors of RTE activity that extend healthy life span and delay the onset and progression of neurodegeneration in fly AD models. To do this we will use new methods to examine in Aim 1 how age and AD change RTE expression and mobilization in specific subsets of neurons and glia in the adult fly brain with scRNA-seq and RTE mobilization reporters (in collaboration with Core B and Project 4), in Aim 2 determine how age and AD change the chromatin state and epigenome related to RTEs with sc-ATAC-seq and CUT&RUN (in collaboration with Core B and Project 4), and in Aim 3 use a novel forward genetic screen to identify new genes and physiological pathways that suppress RTE activity in adult fly brains, resulting in extension of life span and delaying the onset and progression of fly AD. In collaboration with Projects 1, 3, and 4 and Core C the mammalian and human homologs of these genes and physiological pathways that suppress fly AD will be tested for their ability to delay the onset and progression of neurodegeneration in mouse AD models and AD-related cellular phenotypes in human neurons and glia in tissue culture.

这个提议的总体目标是利用果蝇模型系统来确定的作用