Animal Disaggregases and Amyloid Contributions to Early Development

动物解聚和淀粉样蛋白对早期发育的贡献

• 批准号: 2324378
• 负责人: Bryan Phillips
• 金额: $ 77.5万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-15 至 2026-09-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2324378&HistoricalAwards=false
• 关键词: Animal; Disaggregases; Amyloid; Contributions; Early

Neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS, and Huntington’s disease pose a serious healthcare and societal challenge with an estimated prevalence of 7 million cases in the US. These are protein misfolding diseases in which the combination of environment, stress, and aging trigger the conversion of normal proteins into non-functional and deleterious aggregates known as amyloids whose accumulation over time leads to neuronal death. One overlooked but critical challenge for treating toxic aggregates is that protein aggregation is also adaptive, serving vital biological functions such as long-term memory, storage of peptide hormones, and melanin polymerization in animals. It is now also clear that protein aggregates are widespread in normal animal development and their mis-regulation upon introducing non-native proteins capable of disentangling aggregates results in developmental defects. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by a novel class of chaperones which may be key to aggregate processing during animal development. Understanding the regulation of developmentally important aggregates will lead to insights into aggregate-based pathologies and novel developmental mechanistic strategies utilizing functional protein aggregates to regulate cell fate specification. The Broader Impact activities include developing new inquiry-based learning activities to increase gender and minority diversity in STEM fields and implementing an annual 6-week Ambassador in Training Program (ATP) to train a class of ~10 undergraduates in science communication so they can lead enhanced Departmental tours to visiting potential students and their families.The PIs recently identified multiple specific amyloid bodies during the early stages of animal development supporting the hypothesis that animal aggregates are an important component of early development. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by the ABCF proteins which have been previously demonstrated to affect aggregation reporters and native prions in yeast, resolubilization of denatured proteins in vitro, and amyloid processing during animal development. The finding that amyloid aggregates are widespread in early development prompted a new way of thinking about and investigating amyloid aggregates in development. This proposal capitalizes on the complementary and synergistic experimental advantages of C. elegans and S. cerevisiae to test the hypothesis that ABCF proteins are novel, well-conserved and heretofore underappreciated disaggregases that regulate proteostasis in yeast and membrane-less organelle formation in animals, thereby controlling the soluble, functional proteome in a cell fate-specific manner. Aim 1 tests the role of ABCF genes in tissue and cell type specificity of aggregation during animal development. Aim 2 characterizes the role of ABCF in regulating RNA processing (P) body constituent aggregation in worms and yeast, and Aim 3 determines the mechanism of action of Abcf proteins as chaperones. Together, these aims describe a comprehensive examination of how amyloids and their dedicated disaggregases serve as novel regulators of key events in early animal development including storage, propagation, and distribution of maternal and zygotically synthesized proteins that can be released as required. This project is jointly funded by IOS/Developmental Systems Cluster and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

神经退行性疾病在内，包括阿尔茨海默氏症，帕金森氏症，ALS和亨廷顿氏病带来严重的医疗保健和社会挑战，估计在美国占700万例。这些是蛋白质错误折叠疾病，其中环境，压力和衰老的结合触发了正常蛋白的转化为非功能性和有害骨料，称为淀粉样蛋白，其积累会随着时间的流逝导致神经元死亡。治疗有毒骨料的一个被忽视但至关重要的挑战是蛋白质聚集也是适应性的，具有重要的生物学功能，例如长期记忆，肽马的储存和动物中的黑色素聚合。现在也很明显，蛋白质聚集体在正常动物发育中广泛存在，并且在引入能够解散聚集体的非母蛋白时进行的错误调节会导致发育缺陷。该提案的目的是表征早期发育过程中淀粉样蛋白聚集体的存在和作用，并通过一类新型的伴侣进行调节，这可能是动物发育过程中骨料加工的关键。了解发展非常重要的聚集体的调节将导致对基于骨料的病理的见解和利用功能蛋白聚集体调节细胞脂肪规范的新型发育机械策略。更广泛的影响活动包括开发新的基于询问的学习活动，以增加STEM领域的性别和少数群体多样性，并实施一年一度的为期6周的培训计划（ATP），以训练〜10个〜10年级的科学沟通本科生，以便他们可以领导增强的部门旅行以访问潜在的学生及其家人。早期发展。该提案的目的是表征早期发育过程中淀粉样蛋白聚集体的存在和作用，并调查其对ABCF蛋白的调节，而ABCF蛋白的调节先前已被证明会影响酵母中的聚集报告者和天然prions，在动物发育过程中在体外分辨出酵母菌的分解蛋白质和淀粉样蛋白。淀粉样蛋白聚集体在早期开发中广泛的发现促使了一种新的思考和研究开发淀粉样蛋白骨料的方式。该提案资本利用了秀丽隐杆线虫和酿酒酵母的完整而协同的实验优势，以检验以下假说：ABCF蛋白是新颖，保存良好的和迄今为止未经充分的分解酶，可调节酵母和无膜的蛋白质蛋白stas在动物中的蛋白质抗激酶，从而在动物中均具有固体蛋白质，从而构成了稳固的蛋白酶。 AIM 1测试ABCF基因在动物发育过程中聚集的组织和细胞类型特异性中的作用。 AIM 2字符在蠕虫和酵母中ABCF在调节RNA加工（P）身体一致性聚集中的作用，AIM 3决定了ABCF蛋白作为伴侣的作用机理。这些目标共同描述了淀粉样蛋白及其专门的分类酶如何作为早期动物发育中关键事件的新型调节剂，包括储存，繁殖和分布孕产妇和合子合成的蛋白质，这些蛋白质可以根据需要释放。该项目由iOS/开发系统集群和启发竞争性研究的既定计划共同资助（EPSCOR）。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响评估审查标准，认为通过评估被认为是宝贵的支持。