Tailor-Made Molecular Chaperones to Target Protein Misfolding

针对蛋白质错误折叠的定制分子伴侣

基本信息

批准号：
10717818
负责人：
Shu-ou Shan
金额：
$ 54.14万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717818
关键词：
Age Aging Alzheimer&apos s Disease Amyloid beta-42 Amyloid beta-Protein Amyloid deposition Animal Model Behavioral Biochemical Biological Models Brain C-terminal Cell Aging Cell Survival Cell model Cells Chromatography Cognition Disorders Cytoprotection Data Dementia Directed Molecular Evolution Disease Disease Progression Elderly Evolution Failure Fluorescence Generations Goals In Vitro Infusion procedures Kinetics Link Methods Modeling Molecular Molecular Chaperones Mus Neurodegenerative Disorders Neurons Proteins Quality Control Research Specificity System Testing Toxic effect Toxin Transgenic Mice Transmission Electron Microscopy Up-Regulation abeta accumulation age related amyloid formation antitoxin brain dysfunction cofactor cognitive function efficacy testing experimental study hyperphosphorylated tau in vitro testing in vivo insight interest neuroinflammation novel novel strategies novel therapeutic intervention protein aggregation protein aminoacid sequence protein misfolding small molecule tau Proteins

项目摘要

Project Summary Numerous aging-associated neurodegenerative diseases are rooted in the misfolding of proteins and the generation of toxic protein aggregates, with Alzheimer's disease (AD) being the most prevalent form of dementia characterized by the aggregation of the amyloid beta peptide (Aβ) and hyperphosphorylated tau. Few effective strategies are currently available for most of these diseases. In this proposal, we will test the hypothesis that novel molecular chaperones can be evolved to recognize and target aggregation-prone proteins and ameliorate their associated toxicity, thus providing a new approach to intervene in protein misfolding diseases. Using Aβ as the model substrate, our specific goal is to provide proof-of-principle for a new platform for the directed evolution of molecular chaperones that can protect Aβ sequences from aggregation. The efficacy of the evolved chaperones in ameliorating Aβ toxicity will be tested in vitro and in vivo. The proposed studies will establish a new, facile, and broadly applicable approach to evolve novel molecular chaperones tailored to specific aggregation-prone target proteins and thus broadly impact diverse diseases rooted in protein misfolding. The evolved TMMCs are expected to achieve a specificity that is normally unattainable by other approaches, such as small molecules or general chaperone upregulation, and can supplement the reduced capacity of the cellular chaperone network during aging to protect neuronal cells from toxic protein aggregates.

项目概要许多与衰老相关的神经退行性疾病都根源于神经元的错误折叠蛋白质和有毒蛋白质聚集体的产生，与阿尔茨海默病 (AD) 是最常见的痴呆症形式，其特征是淀粉样蛋白 β 肽 (Aβ) 和过度磷酸化 tau 蛋白很少有有效的策略。目前可用于大多数此类疾病。在本提案中，我们将测试假设新的分子伴侣可以进化来识别和靶向易于聚集的蛋白质并改善其相关毒性，从而提供了一种新的使用 Aβ 作为模型底物干预蛋白质错误折叠疾病的方法，我们的具体目标是为定向的新平台提供原理验证可以保护 Aβ 序列免于聚集的分子伴侣的进化。进化的伴侣在改善 Aβ 毒性方面的功效将在体外进行测试拟议的研究将建立一种新的、简便且广泛适用的方法。进化针对特定聚集倾向的新型分子伴侣的方法靶向蛋白质，从而广泛影响源于蛋白质错误折叠的多种疾病。进化后的 TMMC 有望实现通常无法达到的特异性通过其他方法，例如小分子或一般伴侣上调，以及可以补充老化过程中细胞伴侣网络容量的减少保护神经元细胞免受有毒蛋白质聚集体的侵害。