Network and cellular vulnerability to pathological protein progression

网络和细胞对病理性蛋白质进展的脆弱性

• 批准号: 10446480
• 负责人: Michael Henderson
• 金额: $ 49.16万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446480
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anatomy; Animal Model; Atlases; Behavior; Brain; Brain Pathology; Brain region; Cells; Clinical; Complex; Computer Models; Data; Dementia; Dementia with Lewy Bodies; Development; Diffusion; Disease; Disease Progression; Evaluation; Gene Expression; Hippocampus (Brain); Human; Immunofluorescence Immunologic; In Situ Hybridization; Individual; Injections; Knock-in; Knock-in Mouse; Lewy Body Disease; Maps; Mission; Modeling; Molecular; Molecular Profiling; Mus; Nature; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Patients; Persons; Population; Proteins; Research; Resolution; Resources; Seeds; Senile Plaques; Testing; Time; Treatment Efficacy; United States; United States National Institutes of Health; Wild Type Mouse; Work; alpha synuclein; base; beta amyloid pathology; cerebral atrophy; connectome; disease prognosis; efficacy evaluation; extracellular; human model; improved; insight; molecular marker; network models; novel; novel therapeutic intervention; protein aggregation; spatiotemporal; tau Proteins; tau aggregation; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT Over 6.5 million people in the United States currently live with progressive neurodegenerative Alzheimer’s disease (AD) and related dementias including dementia with Lewy bodies (DLB), yet no treatments to stop their progression are available. The presence of aggregated proteins in the brain (tau, amyloid β (Aβ), and α- synuclein) is thought to underlie disease, and clinical overlap in presentation of these diseases associates with the presence of more than one type of pathology. The factors influencing cellular and network vulnerability to each individual pathology or co-occurring pathologies are not well-understood. A proper understanding of vulnerability in the context of co-pathologies is necessary for the development and evaluation of novel disease- modifying treatments. This project will test the hypothesis that progression of intracellular α-synuclein and tau pathologies are bound by neuroanatomical connectivity but influenced by network and cell-level vulnerability. Network and cell-level vulnerability may also be influenced by additional factors such as the presence of co-pathologies, including extracellular amyloid β (Aβ) plaques. To test this hypothesis, the following aims will be pursued: (i) progression of α-synuclein and tau pathologies will be mapped in wildtype mice bearing single or multiple pathologies at high resolution using registration to a common neuroanatomical atlas, and network parameters of progression will be assessed with computational modeling (Specific Aim 1); quantitative pathology and network analysis will be utilized to assess the impact of Aβ plaques on the development, spread, and network vulnerability to α-synuclein and tau co-pathology in knock-in mice that express human tau and develop Aβ plaques and in a time-dependent manner (Specific Aim 2); spatial transcriptomics of human AD brain, DLB brain, and mouse co-pathology brain will be used to determine unique molecular signatures of neurons vulnerable to α-synuclein or tau pathologies. Vulnerability signatures will be validated with combined in situ hybridization-immunofluorescence and integrated with network vulnerability and regional gene expression to develop and evaluate a model of human co-pathology progression as a resource for understanding disease progression and evaluating therapeutic efficacy (Specific Aim 3). The proposed research is expected to improve our understanding of the spatiotemporal progression of co- pathologies and to develop improved tools to evaluate efficacy of novel therapeutic strategies that could slow the progression of neurodegenerative diseases.

项目概要/摘要 目前美国有超过 650 万人患有进行性神经退行性阿尔茨海默病 疾病（AD）和相关痴呆症，包括路易体痴呆（DLB），但尚无治疗方法可以阻止其发生 进展是可用的。大脑中存在聚集蛋白（tau、β 淀粉样蛋白 (Aβ) 和 α- 突触核蛋白）被认为是疾病的根源，这些疾病的临床表现重叠与 存在不止一种病理类型。影响蜂窝和网络脆弱性的因素 每种单独的病理学或同时发生的病理学尚未被充分理解。正确认识 共同病理背景下的脆弱性对于新疾病的开发和评估是必要的。 修改治疗方法。 该项目将检验细胞内 α-突触核蛋白和 tau 病理学进展受到限制的假设 受神经解剖学连接性影响，但受网络和细胞级脆弱性影响。网络和小区级 脆弱性还可能受到其他因素的影响，例如共病的存在，包括 细胞外β淀粉样蛋白（Aβ）斑块。为了检验这一假设，将追求以下目标：（i）进展 α-突触核蛋白和 tau 病理学将在具有单一或多种病理学高水平的野生型小鼠中进行绘制 使用注册到共同的神经解剖图谱进行分辨率，并且进展的网络参数将是 通过计算模型进行评估（具体目标 1）；定量病理学和网络分析将 用于评估 Aβ 斑块对 α-突触核蛋白的发育、扩散和网络脆弱性的影响 表达人类 tau 蛋白并形成 Aβ 斑块的敲入小鼠中的 tau 蛋白共同病理学，并且呈时间依赖性 方式（具体目标 2）；人类 AD 脑、DLB 脑和小鼠共病理脑的空间转录组学 将用于确定易受 α-突触核蛋白或 tau 病理影响的神经元的独特分子特征。 漏洞特征将通过原位杂交-免疫荧光和集成进行验证 利用网络脆弱性和区域基因表达来开发和评估人类共同病理学模型 进展作为了解疾病进展和评估治疗效果的资源（具体 目标3）。 拟议的研究预计将提高我们对共同的时空进展的理解 病理学并开发改进的工具来评估可能减缓的新治疗策略的功效 神经退行性疾病的进展。