Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration

描述（由申请人提供）：衰老增加神经变性的风险。强有力的证据表明，聚集介导的蛋白质毒性是许多临床重要疾病（包括阿尔茨海默病）神经退行性变的原因，尽管其病因尚不清楚。新出现的遗传数据表明，衰老过程通过信号通路与蛋白质稳态的保真度有关，包括恢复或处理错误折叠或聚集蛋白质的能力。总的来说，这个项目致力于实现两个目标：1)了解保护生物体免受蛋白质聚集的途径的有机体、细胞生物学和分子基础；2)确定这些途径是如何随着生物体的衰老而受到损害的。凯利实验室将专注于途径的生化表征和解聚酶活性的潜在分子决定因素，解聚酶活性似乎可以防止秀丽隐杆线虫和阿尔茨海默氏症小鼠模型以及人类细胞中的年龄性蛋白质毒性，他们将测试淀粉样蛋白形成是一个构成过程的假设。Balch实验室将建立衰老细胞模型，以探索年龄依赖性变化在胞外和内吞APR和Abeta加工中的作用，这些变化似乎有助于蛋白质毒性，并将利用他们的专业知识来干扰胞外和内吞途径，以了解Abeta蛋白质毒性的发生。迪林实验室将利用遗传、蛋白质组学和生物信息学方法以及阿尔茨海默病的动物模型来了解衰老相关的信号通路和下游决定因素如何以及哪些影响蛋白质毒性，他们将在蠕虫阿尔茨海默病模型中进行Abeta聚集体结构毒性评估。生物信息学、蛋白质组学、神经科学和神经病理学核心都与这些项目中的两个或多个密切相关，而这些项目本身又是高度相互依存的。该项目获得的结果不仅将深入了解衰老与神经退行性疾病之间的关系，而且应该为开发与年龄相关的神经退行性疾病的治疗策略提供必要的信息。

DESCRIPTION (provided by applicant): Aging increases the risk of neurodegeneration. Strong evidence implicates aggregation-mediated proteotoxicity as the cause of neurodegeneration in numerous clinically important diseases, including Alzheimer's disease, although the etiology is unclear. Emerging genetic data suggest that the aging process is linked by signaling pathways to the fidelity of protein homeostasis, including the ability to recover or dispose of misfolded or aggregated proteins. Overall this program project strives to meet two goals: 1) to understand the organismal, cell biological and molecular bases for the pathways that protect organisms from protein aggregation, and 2) to determine how these pathways become compromised as an organism ages. The Kelly Laboratory will focus on the biochemical characterization of the pathway(s) and the underlying molecular determinants of the disaggregase activity that appears to protect against age onset proteotoxicity in C. elegans and murine models of Alzheimer's and in human cells and they will test the hypothesis that amyloidogenesis is a constitutive process. The Balch Laboratory will generate senescence cell models to probe the role of age-dependent changes in exocytic and endocytic APR and Abeta processing that appear to contribute to proteotoxicity and will employ their expertise to perturb the exocytic and endocytic pathways to understand the genesis of Abeta proteotoxicity. The Dillin Laboratory will utilize genetic, proteomic and bioinformatics approaches and animal models of Alzheimer's disease to understand how and which aging-associated signaling pathways and downstream determinants affect proteotoxicity and they will carry out Abeta aggregate structure toxicity assessments in the worm Alzheimer's model. The bioinformatics, proteomics and neurosciences and neuropathology cores are each intimately associated with two or more of these projects that are themselves highly interdependent. The results obtained from this project will not only provide insight into the relationship between aging and neurodegeneration, but should provide the information necessary to develop therapeutic strategies for age-associated neurodegenerative diseases.