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

总结声明负责路易病理 (LP) 形成、成熟和清除的细胞过程人类疾病组织仍然未知，部分原因是缺乏捕获 LP 的技术长期目标是确定核心细胞环境中的相互作用。负责人脑中 LP 的过程并找到发展疾病的治疗靶点该提案的目的是确定 LP 的作用。突触核蛋白病的发生和进展中的相互作用是核心假设。分子 LP 相互作用是临床突触核蛋白病表型的主要决定因素我们提出的研究的基本原理是确定 LP 之间的相互作用。患病大脑的神经轴将揭示那些对人类负责的核心病理过程突触核蛋白病并提供有关这些过程如何定义的具体分子描述，区分和治疗临床突触核蛋白病的中心假设将在两个特定的情况下进行检验。目标：1) 确定人类突触核蛋白病大脑中的 LP 相互作用；2) 研究 LP 相互作用随着突触核蛋白病的发展，我们将通过啮齿动物大脑的神经轴来测试这些目标。创新的原位邻近标记技术克服了以前的技术限制，提供对 LP 的清晰分子理解这项研究意义重大，因为它将提供一个详细了解 LP 相互作用，这应该成为未来疾病修饰的目标拟议研究的预期结果是为该领域提供公正的治疗。这些结果解释了人类患病大脑和突触核蛋白病模型中的 LP 相互作用。将产生立竿见影的积极影响，因为它们将提供细胞/分子的“全局” 对人类突触核蛋白病的理解目前还无法实现，但对于人类突触核蛋白病的进展至关重要场地