PROTEOMIC MAPPING OF PATHOLOGICAL INTERACTIONS ACROSS THE SYNUCLEINOPATHY BRAIN

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 完整细胞环境中的相互作用。长期目标是确定核心细胞 负责人脑中 LP 的过程并找到发展疾病的治疗靶点 修改突触核蛋白病的治疗方法。该提案的目的是确定 LP 的角色 突触核蛋白病的发生和进展中的相互作用。中心假设是核心 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 疾病进展。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导致人类健康的核心病理过程 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。中心假设将在两个特定的方面进行检验 目标：1) 确定人类突触核蛋白病大脑中的 LP 相互作用； 2) 调查 LP 交互 当突触核蛋白病发生时，它会穿过啮齿动物大脑的神经轴。我们将通过使用我们的 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有清晰的分子认识。拟议的研究意义重大，因为它将提供 详细了解 LP 相互作用，这应该成为未来疾病修饰的目标 疗法。拟议研究的预期结果是为该领域提供公正的 解释了人类患病大脑和突触核蛋白病模型中 LP 相互作用的情况。这些结果 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 领域

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