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Define molecular events driving selective neuronal death in multiple neurodegenerative diseases by snRNA-seq

通过 snRNA-seq 定义多种神经退行性疾病中驱动选择性神经元死亡的分子事件

基本信息

批准号：
10323684
负责人：
Jinbin Xu
金额：
$ 15.75万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323684
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia American Archives Area Attention Automobile Driving Basal Ganglia Biological Biological Markers Biology Brain Candidate Disease Gene Cell Nucleus Cells Characteristics Clinical Cognitive Collaborations Data Dementia Development Disease Disease Progression Event Freezing Funding Gene Expression Heterogeneity Hippocampus (Brain)Human Immunotherapy Laboratories Ligands Methods Microglia Molecular Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuroimmune Neurons Parkinson Disease Parkinsonian Disorders Pathologic Pathology Pathway Analysis Pathway interactions Patients Population Predisposition Prevention Process Proteins Receptor Signaling Regulation Research Research Personnel Research Project Grants Role Small Nuclear RNA Specimen Substantia nigra structure Technology Time Tissues Tremor United States National Institutes of Health brain tissue cell type cognitive function cohort disorder control dopaminergic neuron gene regulatory network genome-wide improved insight longitudinal analysis macrophage molecular marker motor learning motor symptom neuroinflammation neuron loss new therapeutic target next generation novel prevent programs single-cell RNA sequencing tool transcriptome transcriptome sequencing transcriptomics treatment strategy

项目摘要

Project Summary Despite decades of research, currently the mechanisms of neurodegeneration in Alzheimer’s disease (AD) and Parkinson Disease (PD) remain controversial and there are no therapies can prevent, slow, or halt disease progression. Neurodegenerative diseases have two fundamental general characteristics. 1) The pathology associated with the disease only affects particular neurons (‘selective neuronal vulnerability’); 2) The pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The discovery of key pathways that regulate this differential susceptibility of neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. However, the mechanisms underlying selective neuronal and regional vulnerability have been difficult to dissect because of our limited ability to distinguish different neuronal subpopulations. Loss of dopaminergic neurons in the SN is a hallmark of PD which underlies the parkinsonian motor symptoms such as rigidity and tremor. Neuronal loss also occurs in the SN of AD [8, 9], however, often without co-occurring parkinsonian motor symptoms. Dopaminergic neurons within the SN are highly heterogeneous [10] and the loss of the dopaminergic neurons in PD is heterogeneous across different axes [11-14]. It is unclear whether the same population of neurons were lost in AD and PD and whether the mechanisms of neuronal loss are shared between the two diseases. Neuroinflammation - activation of the neuroimmune cells (e.g. microglia) into proinflammatory states - are shared pathological contributors in AD and PD. However, the molecular identity of different microglia subpopulations and the role of neuroinflammation in the selective neuronal death remain unclear. Therefore, we propose to use single nucleus RNA-seq (snRNA-seq), an unbiased approach to identify and characterize distinct cell populations in tissues, to dissect the mechanisms underlying selective neuronal death. Specifically, our specific aims are: Aim 1: Characterize and validate cellular heterogeneity, cellular and transcriptomic changes of neuron and microglia from the SN brain tissues of AD, PD patients and age-matched controls. Aim 2: Dissect the mechanisms of cell composition and transcriptome dysregulation in AD and PD. Our study will provide 1) molecular markers and tools for targeted neuronal and microglia subpopulation isolation and manipulation; 2) better understanding of the dynamic change of different neuronal and microglia subpopulation, their transcriptomic changes and the putative regulatory mechanisms in AD and PD; 3) high- confidence new candidate genes and pathways as targets to develop effective immunotherapies or neuroprotective strategies.

项目总结