Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration

衰老、Abeta 蛋白毒性和神经退行性变之间的分子机制

• 批准号: 7563376
• 负责人: JEFFERY W KELLY
• 金额: $ 225.11万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563376
• 关键词: Molecular; Mechanisms; linking; Aging; Abeta

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.

描述（由申请人提供）：衰老增加了神经退行性的风险。有力的证据表明，聚集介导的蛋白毒性是许多临床上重要疾病（包括阿尔茨海默氏病）中神经退行性的原因，尽管病因尚不清楚。新兴的遗传数据表明，衰老过程通过信号传导途径与蛋白质稳态的信号联系在一起，包括恢复或处置错误折叠或聚集的蛋白质的能力。总的来说，该计划项目旨在实现两个目标：1）了解保护生物免受蛋白质聚集的途径的生物，细胞生物学和分子碱基，以及2）确定这些途径如何随着生物体年龄的年龄而受到损害。凯利实验室将着重于途径的生化表征以及分解酶活性的基础分子决定因素，这些分解酶活性似乎可以防止在阿尔茨海默氏菌和人类细胞的耶和华类模型中预防年龄发作蛋白毒性，并且它们将测试乳突组发生的假设是乳腺癌的。 Balch实验室将产生衰老细胞模型，以探测依赖年龄的外生型和内吞APR和ABETA加工的作用，这些变化似乎有助于蛋白毒性，并将采用其专业知识来扰动外生型和内吞途径，以了解Abeta蛋白毒性的生成。 DILLIN实验室将利用阿尔茨海默氏病的遗传，蛋白质组学和生物信息学方法和动物模型，以了解如何以及哪些与衰老相关的信号通路和下游决定因素会影响蛋白质毒性，并且它们将在蠕虫中进行ABETA ABETA聚集毒性评估Alzheimer的模型。生物信息学，蛋白质组学和神经科学和神经病理学核心都与这些本身高度相互依存的两个或多个项目密切相关。从该项目获得的结果不仅将洞悉衰老与神经变性之间的关系，而且还应提供为与年龄相关的神经退行性疾病制定治疗策略所必需的信息。