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Functional analysis of glia in tauopathy

tau蛋白病中神经胶质细胞的功能分析

基本信息

批准号：
10523584
负责人：
MEL B FEANY
金额：
$ 253.16万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523584
关键词：
Adult Affect Aging Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Binding Proteins Biochemical Pathway Biological Assay Biological Models Biology Brain Candidate Disease Gene Cell Nucleus Cells Cellular biology Chromosome 17 Clinical Complex Data Deposition Development Disease Drosophila genus FTD with parkinsonism Gene Expression Genes Genetic Genetic Models Genetic Variation Genetic study Gliosis Health Human Human Amyloid Precursor Protein Impaired cognition Influentials Investigation Link Longevity Mediating Methods Microtubules Modeling Molecular Molecular Genetics Molecular Target Morphology Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Pathologic Pathology Pathway interactions Patients Peptides Play Proteins Proteomics RNA Splicing Risk Factors Role Seminal Senile Plaques System Systems Analysis Systems Biology Tauopathies Testing Toxic effect Transgenic Mice Transgenic Organisms Work base cellular targeting computerized tools design experimental study extracellular familial Alzheimer disease fly gene product genetic approach genetic association genetic manipulation genome wide association study genome-wide human disease informatics tool insight nervous system disorder neurotoxicity novel progressive neurodegeneration screening tau Proteins tau aggregation therapy development tool transcriptome sequencing transcriptomics

项目摘要

Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction. Classic neuropathological features of the disease include the formation of extracellular amyloid plaques, intraneuronal deposition of abnormally phosphorylated and aggregated tau protein into neurofibrillary tangles, and gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Alzheimer’s disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Alzheimer’s-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence tau neurotoxicity in aging adult brains. In proof of principle studies, we have validated a novel system for studying non-cell autonomous neurodegeneration in tauopathy and show that our assay system works in the context of unbiased screening. In addition, based on the observation that many genes implicated in Alzheimer’s disease through genome wide genetic association studies (GWAS) are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these GWAS-derived gene candidates in fly glia on tau-induced neurotoxicity. To additionally connect our genetic model experiments with the authentic human disease, we will use state-of-the-art informatics tools to integrate functional genetic data with Alzheimer’s disease transcriptomics and proteomics. Since our systems analysis will be performed on a glial subtype-specific basis our studies can not only outline glial networks modulating the toxicity of tau to neurons, but also provide functional insight into newly defined glial subtypes. Our studies will develop fundamental insights into glia cell biology in health and disease and will expand the array of cellular and molecular targets relevant for therapy development in Alzheimer’s disease and related neurodegenerative disorders.

阿尔茨海默病是最常见的神经退行性疾病，临床表现为