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.

项目概要尽管经过了数十年的研究，目前阿尔茨海默氏症的神经退行性机制仍不清楚疾病（AD）和帕金森病（PD）仍然存在争议，并且没有治疗方法可以预防、减缓或阻止疾病进展有两个基本原则。一般特征 1) 与疾病相关的病理学仅影响特定的特征。神经元（“选择性神经元脆弱性”）；2）病理随着时间的推移而恶化，影响更大以刻板和可预测的方式发现调节的关键途径。神经元对退化的这种不同的敏感性对于发现新的药物靶点和有前景的神经保护治疗策略的开发。然而，选择性神经和区域脆弱性的潜在机制已被证实由于我们区分不同神经亚群的能力有限，因此很难解剖。 SN 中多巴胺能神经元的丧失是 PD 的一个标志，它是帕金森病的基础 AD 的 SN 中也会出现运动症状，如强直和震颤 [8, 9]。然而，通常没有同时发生的帕金森运动症状。 SN 具有高度异质性 [10]，PD 中多巴胺能神经元的损失不同轴上的异质性 [11-14] 目前尚不清楚是否有相同的神经元群体。 AD 和 PD 中的神经丢失机制以及神经丢失的机制是否在 AD 和 PD 之间共享两种疾病——神经免疫细胞（例如小胶质细胞）的激活。促炎症状态 - 是 AD 和 PD 的共同病理因素。不同小胶质细胞亚群的分子特性以及神经炎症在因此，选择性神经死亡仍不清楚，我们建议使用单核RNA-seq。 (snRNA-seq)，一种识别和表征不同细胞群的无偏见方法组织，剖析选择性神经死亡的机制。目标是：目标 1：表征和验证细胞异质性、细胞和 AD、PD SN 脑组织神经元和小胶质细胞转录组变化目标 2：剖析细胞组成的机制。 AD 和 PD 中的转录组失调。我们的研究将提供 1) 分子标记。以及针对目标神经和小胶质细胞亚群分离和操作的工具 2) 更好；了解不同神经和小胶质细胞亚群的动态变化及其 AD 和 PD 中的转录组变化和假定的调节机制 3) 高- 相信新的候选基因和途径作为开发有效免疫疗法的目标或神经保护策略。