PROTEOMIC MAPPING OF PATHOLOGICAL INTERACTIONS ACROSS THE SYNUCLEINOPATHY BRAIN

摘要报表 路易氏病变(LP)形成、成熟和清除的细胞过程 人类疾病组织仍不为人所知，部分原因是缺乏捕捉LP的技术 在完整的细胞环境中的相互作用。长期目标是确定核心-细胞 人类大脑中负责LP的过程，并找到治疗疾病的靶点 修改联核症的治疗方法。这项建议的目标是确定LP的角色 联体核病发生和发展过程中的相互作用。中心假设是核心 分子LP相互作用是临床共核病表型和 疾病的发展。我们建议的研究的基本原理是，确定LP的相互作用 病变大脑的神经轴将揭示人类的核心病理过程 并提供关于这些过程如何定义的具体分子描述， 辨别和治疗临床联体核病。核心假设将在两个具体的方面进行检验 目的：1)确定人类突触核病脑内LP的相互作用；2)研究LP的相互作用 穿过啮齿动物大脑的神经轴，随着联核症的发展。我们将使用我们的 创新的原位邻近标记技术，克服了以前的技术限制，以提供 对LP有明确的分子认识。拟议的研究具有重要意义，因为它将提供一种 对LP相互作用的详细了解应成为未来疾病修改的目标 治疗学。拟议研究的预期结果是为该领域提供一个公正的 在人类患病的大脑和联核症模型中LP相互作用的说明。这些结果 将产生立竿见影的积极影响，因为它们将提供一幅细胞/分子的“全景图” 对人类共核病的理解目前尚不能获得，但对在 字段

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