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Molecular impact of endolysosomal dysfunction on neuron-glia communication pathways

内溶酶体功能障碍对神经元-胶质细胞通讯途径的分子影响

基本信息

批准号：
10538113
负责人：
Nader Francis Morshed
金额：
$ 6.72万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-29 至 2025-04-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538113
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid beta-Protein Precursor Astrocytes Binding Binding Proteins Brain Brain region Cell physiology Cell surface Cells Communication Complement Complement component C4 Complex Dementia Disease Progression Endosomes Environment Event Functional disorder Genes Genetic Genetic Engineering Genetic Risk Genetic Transcription Genetic study Genetically Engineered Mouse Gliosis Goals Healthcare Systems Hippocampus (Brain)Human Impairment Inflammation Lead Learning Link Mediating Microglia Molecular Mus Mutate Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuroglia Neuroimmune Neurons Organelles Pathogenesis Pathogenicity Pathology Pathway interactions Patients Production Proteins Proteome Proteomics Recycling Research Risk Role Signal Pathway Signal Transduction Synapses System Technology Testing Time amyloid precursor protein processing brain cell cell type conditional knockout cytokine dementia risk experimental study glial activation human model human pluripotent stem cell in vivo insight lens macrophage molecular pathology novel prevent protein aggregation protein transport receptor receptor binding risk variant scaffold secretion process stem cell model tau Proteins tool trafficking trans-Golgi Network

项目摘要

Project Abstract Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia worldwide. Despite decades of research, there are few therapies that can delay or prevent AD progression. Retrograde trafficking through retromer-dependent cargo recognition has emerged as a critical cellular process that is mutated or disrupted in patients with AD and other forms of dementia. Conditional knockout of retromer genes in neurons leads to increased secretion of Tau and Amyloid β (Aβ), hallmark protein pathologies linked to AD. This milieu of neuronal-secreted factors leads to inflammation in microglia and astrocytes, two glial cell types thought to influence the progression of neurodegeneration. In this proposal, I aim to study the cascade of events linking neuronal retromer disruption to glial inflammation, characterizing the specific cell state changes involved, and identify the key factors that mediate this effect. I will address this aim using genetically engineered stem cell- derived models of human neurons, microglia, and astrocytes. Microglia also express retromer components and upregulate these factors in AD, yet there are few studies of retromer function specifically in microglia. In Aim 2 I will therefore explore the effects of retromer-related mutations specifically on microglia in the context of early aging in mice, a comparable time point to when dementia manifests in patients with these mutations. I will additionally utilize stem cell models to dissect the functional and signaling changes that are induced in microglia with retromer disruption. Finally, although there have been several studies looking at the effects of retromer on specific receptors, little is known about the systems-level effects of retromer mutations on protein trafficking to the endosomes. To identify retromer-dependent signaling pathways that may be pathogenic, I have developed novel proteomics tools to quantify endosomal proteome changes and will use these tools to compare the effects of different retromer mutations on neuronal and microglial endosomes. The ultimate goal is to understand how retromer disruption affects brain cell states and leads to pathogenic signaling changes.

项目摘要