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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，其临床特征是认知功能障碍该疾病的典型神经病理学特征包括细胞外淀粉样斑块，异常磷酸化和聚集的tau蛋白的神经元内沉积神经纤维缠结和神经胶质增生。神经胶质病理学通常被认为是继发性的，或反应性的变化。然而，最近在理解正常和病理性神经胶质生物学方面的进展，相反，这表明神经胶质可能在神经系统疾病中发挥积极作用，包括阿尔茨海默氏病。在这里，我们采用遗传学的方法来定义介导神经胶质细胞对神经元的影响的蛋白质和途径。阿尔茨海默氏症相关的神经变性利用先进的分子和遗传工具，短寿命和保守的神经胶质生物学，我们将确定神经胶质蛋白和途径，影响老化成人大脑中tau神经毒性。在原理研究的证明中，我们验证了一种新颖的用于研究tau蛋白病中非细胞自主神经变性的系统，并表明我们的测定系统在无偏筛选的情况下有效。此外，根据观察，许多基因通过全基因组遗传关联研究（GWAS）发现，主要或基本上在神经胶质细胞中，我们将测试上调和下调这些果蝇神经胶质细胞中GWAS衍生的候选基因对tau诱导的神经毒性的影响。为了将我们的基因为了用真实的人类疾病进行模型实验，我们将使用最先进的信息学工具，将功能遗传学数据与阿尔茨海默病转录组学和蛋白质组学相结合。由于我们系统分析将在胶质细胞亚型特异性的基础上进行，我们的研究不仅可以概述胶质细胞，网络调节tau对神经元的毒性，但也提供了新定义的神经胶质细胞的功能洞察。亚型我们的研究将发展神经胶质细胞生物学在健康和疾病的基本见解，扩大与阿尔茨海默病治疗开发相关的细胞和分子靶点阵列和相关的神经退行性疾病。