Molecular Mechanisms of SOD1-linked ALS (P01)

描述（由申请人提供）：本项目汇集了五位具有不同专业知识和实验能力的研究人员，共同研究sod1相关的家族性肌萎缩性侧索硬化症（fALS）发病机制。众所周知，S0D1多聚体和较大的聚集体与疾病有关，但毒性种类和体内机制仍不清楚。本研究的总体目标是广泛了解聚集在疾病中的作用，进一步表征与突变体S0D1及其聚集相关的生化特性，揭示疾病发生和进展的线索，并利用这一认识开发靶向多聚受体阻滞剂。PPG合作将包括五个主要研究人员，四个项目和一个技术核心。项目1 （Joan Valentine博士）和项目4 （David Eisenberg博士）将采用体外结构和生物物理方法研究S0D1多聚的机制和多聚子的结构，目的是了解多聚的机制和设计聚集抑制剂。项目2 （Martina Wiedau-Pazos博士）将使用干细胞衍生的运动神经元和神经胶质细胞，项目3 （David Borchelt博士）将使用小鼠和细胞培养模型来探测多片段体的毒性，并表征导致疾病的突变体S0D1的变化。后一个项目将特别强调体内金属负荷，因为它与S0D1稳定性有关，以及金属稳态，因为它与细胞毒性有关。核心A （Julian Whitelegge博士）将作为这些调查的骨干，提供和维护必要的仪器和数据传输。项目2和3的疾病模型将用于测试项目1和4的抑制剂的功效。最后，ALS组织将被用作验证发现和测试新假设的来源。

DESCRIPTION (provided by applicant): This Program Project brings together five researchers with very different expertise and experimental capabilities to work together on elucidating the underlying mechanisms of S0D1-linked familial amyotrophic lateral sclerosis (fALS) pathogenesis. It is well established that S0D1 multimers and larger aggregates are associated with disease but the toxic species and in vivo mechanism remain unknown. The overall goals of this proposal are to gain an extensive understanding of the role of aggregation in disease, to characterize further the biochemical properties associated with mutant S0D1 and its aggregation, to uncover clues about the initiation and progression of disease, to exploit this understanding to develop targeted blockers of multimerization. The PPG collaboration will encompass five primary investigators with four projects and a technical Core. Projects 1 (Dr. Joan Valentine) and 4 (Dr. David Eisenberg) will take an in vitro structural and biophysical approach to studying the mechanism of S0D1 multimerization and the structures of the multimers, with the goals of understanding the mechanism(s) of multimerization and designing inhibitors of aggregation. Project 2 (Dr. Martina Wiedau-Pazos) will use stem cell-derived motor neurons and glia and project 3 (Dr. David Borchelt) will use a mouse,and cell culture models to probe the toxicity of multimers and to characterize the changes in mutant S0D1 that lead toward disease. A particular emphasis on the latter project will be toward in vivo metal loading as it pertains to S0D1 stability, and metal homeostasis as it pertains toward cellular toxicity. Core A (Dr. Julian Whitelegge) will serve as the backbone of these investigations by providing and maintaining the necessary instrumentation and data delivery. Disease models from projects 2 and 3 will be used to test the efficacy of inhibitors from projects 1 and 4. Finally, ALS tissue will be used as a source to validate the findings and test new hypotheses.