Tailor-Made Molecular Chaperones to Target Protein Misfolding

项目摘要 许多与衰老相关的神经退行性疾病的根源在于 蛋白质和有毒蛋白质聚集体的产生，与阿尔茨海默病（AD） 作为最普遍的痴呆形式，其特征在于 淀粉样β肽（Aβ）和过度磷酸化的tau蛋白。很少有有效的策略 目前可用于大多数这些疾病。在本提案中，我们将测试 新的分子伴侣可以进化为识别和靶向的假说 聚集倾向的蛋白质，并改善其相关的毒性，从而提供了一个新的 干预蛋白质错误折叠疾病的方法。以Aβ为模型底物， 我们的具体目标是为定向的新平台提供原理证明。 分子伴侣的进化可以保护Aβ序列免于聚集。的 将在体外测试进化的分子伴侣在改善Aβ毒性中的功效， in vivo.拟议的研究将建立一个新的，简便的，广泛适用的 一种开发适合于特定聚集倾向的新型分子伴侣的方法 靶向蛋白质，从而广泛影响植根于蛋白质错误折叠的各种疾病。 预计进化的TMMC将达到通常无法达到的特异性 通过其他方法，如小分子或一般伴侣上调，和 可以在老化期间补充蜂窝伴侣网络的减少的容量， 保护神经元细胞免受有毒蛋白质聚集的伤害。

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.