From Physiological Liquids to Pathological Gels: Regulation of Protein Phase Separation in Neurodegenerative Disease

 描述(由申请人提供)：病理性蛋白质聚集普遍与神经退行性疾病有关，但其潜在机制很大程度上尚不清楚。最近的开创性工作表明，细胞内的液体相转变在控制具有液体性质的功能性蛋白质组件或颗粒的组装和组织中发挥了作用。这项提议试图检验这样一个假设，即细胞内液相分离的错误调节会导致有害的蛋白质聚集。在指导阶段，目标1试图定义与疾病有关的应激颗粒蛋白的物理化学参数和相图。这一目标将通过应用工程和软物质物理原理以及埃尔鲍姆博士以前开发的独特流变学方法来实现。目的2试图确定在衰老和应激作用下，在体内的液体相、聚集和毒性之间的关系。利用线虫模型系统，这一目标将建立液体蛋白相是否阻止或促进淀粉样蛋白的形成，并获得关于衰老和/或压力是否有助于调节蛋白质组装的洞察。在独立阶段，Aim 3试图确定调控蛋白质组装的分子途径，并进一步解析调控的分子机制。这一目标将通过一种独特的多尺度方法来实现，该方法结合了单分子技术、材料科学方法和生物体水平的审问。总之，这一创新战略将为病理性蛋白质聚集的生物发生提供新的见解，并为旨在预防或减轻神经退行性疾病的健康负担的治疗干预定义新的途径和独特的分子靶点。

 DESCRIPTION (provided by applicant): Pathological protein aggregation is ubiquitously associated with neurodegenerative disease, but the underlying mechanisms are largely unclear. Recent groundbreaking work suggests a role for intracellular liquid phase transitions in governing the assembly and organization of functional protein assemblies or granules with liquid-like properties. This proposal seeks to test the hypothesis that misregulation of intracellular liquid phase separation leads to detrimental protein aggregation. In the mentored phase, Aim 1 seeks to define the physicochemical parameters and phase landscape of stress granule proteins implicated in disease. This aim will be achieved through applying principles of engineering and soft matter physics along with unique rheological methodologies previously developed by Dr. Elbaum. Aim 2 seeks to determine the relationship between liquid phases, aggregation and toxicity in vivo as a function of aging and stress. Using the C. elegans model system, this aim will establish whether liquid protein phases prevent or promote amyloid formation, and garner insight into whether aging and/or stress contribute to regulation of protein assembly. In the independent phase, Aim 3 seeks to identify molecular pathways regulating protein assembly and further resolve the molecular mechanisms underlying regulation. This aim will be achieved through a unique multi-scale approach combining single molecule techniques, material science methodologies, and organismal level interrogation. Together, this innovative strategy will offer novel insight into the biogenesis of pathological protein aggregation, and define new pathways and distinct molecular targets for therapeutic interventions aimed at preventing or reducing the health burdens of neurodegenerative disease.