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PROTEOMIC MAPPING OF PATHOLOGICAL INTERACTIONS ACROSS THE SYNUCLEINOPATHY BRAIN

突触核蛋白病大脑病理相互作用的蛋白质组图谱

基本信息

批准号：
10677783
负责人：
Bryan Killinger
金额：
$ 39.5万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
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：
2022-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677783
关键词：
Antigens Biochemical Biotinylation Brain Brain Diseases Brain region Catalogs Cell physiology Chemicals Clinical Consensus Dementia with Lewy Bodies Development Disease Disease Progression Environment Future Goals Human In Situ Knowledge Label Lewy body pathology Maps Measures Mechanics Microscopy Mission Modeling Molecular Neurodegenerative Disorders Organelles Outcome Parkinson Disease Pathologic Pathologic Processes Pathway interactions Phenotype Process Proteomics Public Health Research Rodent Rodent Model Role Sampling Structure Techniques Testing Therapeutic Time Tissues United States National Institutes of Health alpha synuclein cell injury disability human disease innovation insight nervous system disorder novel novel therapeutic intervention prevent protein protein interaction response synucleinopathy therapeutic development therapeutic target translational model

项目摘要

Summary Statement The cellular processes responsible for Lewy pathology (LP) formation, maturation, and clearance in human disease tissues remain unknown in part because a lack of techniques available to capture LP interactions in the intact cellular environment. The long-term goal is to determine the core-cellular processes responsible for LP in the human brain and find therapeutic targets to develop disease modifying treatments for synucleinopathy. The objective of this proposal is to determine the role of LP interactions in the initiation and progression of synucleinopathies. The central hypothesis is that core molecular LP interactions are the major determinants of clinical synucleinopathies phenotypes and disease progression. Our rationale for the proposed studies is that determining LP interactions across the neuroaxis of the diseased brain will reveal those core pathological processes responsible for human synucleinopathies and offer a concrete molecular description concerning how those processes define, distinguish, and treat clinical synucleinopathies. The central hypothesis will be tested in two specific aims: 1) Determine LP interactions in the human synucleinopathy brain; 2) Investigate LP interactions across the neuroaxis of a rodent brain as synucleinopathy develops. We will test these aims by using our innovative in situ proximity labeling technique that overcomes previous technical limitations, to provide a clear molecular understanding of LP. The proposed research is significant because it will provide a detailed understanding of LP interactions that should be targets for future disease modifying therapeutics. The expected outcome of the proposed research is to provide the field with an unbiased account of LP interactions in the human diseased brain and in models of synucleinopathy. These results will have an immediate positive impact because they will provide a “big picture” cellular/molecular understanding of human synucleinopathies that is currently unavailable but crucial for progress in the field

简要说明路易病理（LP）的形成，成熟和清除的细胞过程，人类患病组织仍然未知，部分原因是缺乏捕获LP的技术在完整的细胞环境中相互作用。长期目标是确定核心细胞负责LP在人脑中的过程，并找到治疗目标，以发展疾病修改突触核蛋白病的治疗方法本建议的目的是确定LP的作用突触核蛋白病的启动和进展中的相互作用。核心假设是，分子LP相互作用是临床共核蛋白病表型的主要决定因素，疾病进展。我们提出的研究的理由是，确定LP之间的相互作用患病大脑的神经轴将揭示那些负责人类疾病的核心病理过程。突触核蛋白病，并提供了一个具体的分子描述，区分和治疗临床突触核蛋白病。中心假设将在两个具体的目的：1）确定人类突触核蛋白病脑中的LP相互作用; 2）研究LP相互作用在啮齿动物大脑的神经轴上发生突触核蛋白病。我们将通过使用我们的创新的原位邻近标记技术克服了先前的技术限制，对LP的分子理解。这项研究意义重大，因为它将提供一个对LP相互作用的详细了解，这些相互作用应成为未来疾病修饰的目标治疗学拟议研究的预期结果是为该领域提供一个公正的在人类患病大脑和突触核蛋白病模型中LP相互作用的帐户。这些结果将立即产生积极的影响，因为它们将提供一个“大图片”细胞/分子了解人类突触核蛋白病，这是目前不可用，但关键的进展，领域