Amyloid Regulatory Networks

淀粉样蛋白调节网络

• 批准号: 1262729
• 负责人: Regina Murphy
• 金额: $ 39万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1262729&HistoricalAwards=false
• 关键词: Amyloid; Regulatory; Networks

CBET-1262729MurphyDiseases such as Alzheimer's, Parkinson's, and diabetes are distinctly different in etiology, symptoms, and progression. Yet they share one common feature: the deposition of proteins on affected organs. The deposited proteins are unique to each disease, and their normal shape and function are distinctly different. Yet, in each case, the proteins undergo a change in shape and structure, causing them to stick together into clumps of fibrillar aggregates. The process of converting normal soluble proteins to insoluble fibrillar aggregates is called amyloidogenesis. The deposits in each disease are comprised mainly of a single protein, unique to each disorder; in other words, the deposits are formed through 'self' association. This self-association arises as a result of the structural features that the proteins adopt at some point during the amyloidogenesis process. These structural features arise in all proteins on the amyloid pathway, at an intermediate point along the pathway, no matter what the disease. The similarity of structural features could lead to 'non-self' association: association between two different proteins that are both at a similar intermediate point. Data with one pair of such proteins, transthyretin (involved in senile systemic amyloidosis) and beta-amyloid (Alzheimer's disease), demonstrate clearly that such non-self association does exist. Furthermore, the binding of transthyretin to beta-amyloid halts beta-amyloid aggregation and, more importantly, prevents beta-amyloid from killing neuron cells. In this project, the examination of non-self association between amyloidogenic proteins will be expanded beyond transthyretin and beta-amyloid. About 100 different pairs of proteins will be probed to determine if the proteins interact. If the answer is yes, experiments will be conducted to define the specific parts of the proteins that are involved in the interaction, and to measure the effect of the interaction on progress along the amyloidogenesis pathway. The hypothesis underlying this project is that a regulatory network exists, that this network contains many amyloidogenic proteins, and that 'non-self' interactions are important in intervening in 'self' interactions. As with transthyretin and beta-amyloid, such 'non-self' interactions may prevent the toxicity that arises due to 'self' interaction. If successful, no longer will scientists think about protein aggregation as an isolated event involving a single protein, but rather, as a network of interacting proteins that co-regulate each other's self-association. Results from this project could contribute innovative new strategies for combating these protein aggregation disorders.

CBET-1262729 Murphy疾病如阿尔茨海默氏症、帕金森氏症和糖尿病在病因、症状和进展方面明显不同。然而，它们有一个共同的功能：蛋白质沉积在受影响的器官上。沉积的蛋白质对每种疾病都是独特的，它们的正常形状和功能也明显不同。然而，在每种情况下，蛋白质都经历了形状和结构的变化，使它们粘在一起形成纤维状聚集体。将正常可溶性蛋白质转化为不溶性纤维状聚集体的过程称为淀粉样蛋白生成。每种疾病中的沉积物主要由每种疾病所特有的单一蛋白质组成;换句话说，沉积物是通过“自我”缔合形成的。这种自缔合是由于蛋白质在淀粉样蛋白生成过程中的某个点所采用的结构特征而产生的。这些结构特征出现在淀粉样蛋白通路上的所有蛋白质中，在通路的中间点沿着，不管是什么疾病。结构特征的相似性可能导致“非自我”关联：两种不同蛋白质之间的关联都处于相似的中间点。一对这样的蛋白质，甲状腺素运载蛋白（涉及老年系统性淀粉样变性）和β-淀粉样蛋白（阿尔茨海默病）的数据清楚地表明，这种非自我关联确实存在。此外，甲状腺素运载蛋白与β-淀粉样蛋白的结合阻止β-淀粉样蛋白聚集，更重要的是，防止β-淀粉样蛋白杀死神经元细胞。在这个项目中，淀粉样蛋白之间的非自身关联的检查将扩展到甲状腺素运载蛋白和β-淀粉样蛋白之外。大约100对不同的蛋白质将被探测，以确定蛋白质是否相互作用。如果答案是肯定的，将进行实验以确定参与相互作用的蛋白质的特定部分，并测量相互作用对淀粉样蛋白生成途径沿着进展的影响。该项目的假设是，存在一个调节网络，该网络包含许多淀粉样蛋白，并且“非自我”相互作用在干预“自我”相互作用中很重要。与甲状腺素运载蛋白和β-淀粉样蛋白一样，这种“非自身”相互作用可以防止由于“自身”相互作用而产生的毒性。如果成功的话，科学家们将不再认为蛋白质聚集是一个涉及单个蛋白质的孤立事件，而是一个相互作用的蛋白质网络，它们共同调节彼此的自我关联。该项目的结果可以为对抗这些蛋白质聚集障碍提供创新的新策略。