ELUCIDATING AN INHIBITORY ROLE OF MAP2 IN TAU FIBRILLIZATION

目前，还没有阻止阿尔茨海默病(AD)进展的药物。这构成了一个 这是一个重要的问题，因为美国有500万人受到影响。Tau纤维的沉积 整个大脑都是这种疾病的病理标志。以纤维为靶点有望实现 治疗性干预。MAP2是一种与Tau高度同源的蛋白质，发现于 陶土矿藏。这项建议的目的是确定MAP2如何调节Tau原纤维的形成。这个 中心假设是MAP2在末端覆盖Tau原纤维，从而抑制原纤维的生长。这一假设 是基于申请者实验室产生的揭示特定相互作用的数据而制定的 在Tau原纤维和MAP2之间。其基本原理是，一旦MAP2的调节作用得到解决，新的 可以开发利用MAP2作为Tau原纤维形成的封闭剂的策略。得到强大的支持 初步数据将通过追求以下三个具体目标来检验中心假设。1)评估 MAP2对AD来源的Tau纤维伸长的抑制作用。2)确定分子机制 MAP2介导的抑制作用。3)确定MAP2如何调节不同Tau原纤维的传播 变形者。这项研究具有创新性，因为它建立了一种具有高序列的内源蛋白质 与牛磺酸同源，作为牛磺酸纤化的一种有效的新抑制剂。这项拟议的研究意义重大，因为它 预计将导致预防和治疗广泛的Tau错误折叠的新策略 疾病包括阿尔茨海默病。这项研究是探索性的，并为未来对 人类肌萎缩侧索硬化症的表型多样性和利用同源基因的新治疗方法 抑制Tau的纤化。

Currently, there are no drugs that halt the progression of Alzheimer's disease (AD). This constitutes an important problem because >5 million people in the United Sates are affected. The deposition of Tau fibrils throughout the brain is a pathological hallmark of the disease. Targeting the fibrils holds promise for therapeutic intervention. MAP2 is a protein that is highly homologous to Tau and is found in close proximity to Tau deposits. The objective of this proposal is to determine how MAP2 modulates Tau fibril formation. The central hypothesis is that MAP2 caps Tau fibrils at the ends and thereby inhibits fibril growth. This hypothesis has been formulated based on data produced in the applicant's laboratory that reveals specific interactions between Tau fibrils and MAP2. The rationale is that once the modulatory roles of MAP2 are resolved, new strategies can be developed that utilize MAP2 as a blocking agent of Tau fibril formation. Supported by strong preliminary data the central hypothesis will be tested by pursuit of the following three specific aims. 1) Evaluate the inhibitory effects of MAP2 on the elongation of AD-derived Tau fibrils. 2) Identify the molecular mechanism of MAP2-mediated inhibition. 3) Determine how MAP2 modulates the propagation of distinct Tau fibril conformers. The research is innovative because it establishes an endogeneous protein with high sequence homology to Tau as a potent new inhibitor of Tau fibrillization. The proposed research is significant because it is expected to lead to new strategies for the prevention and treatment of a wide range of Tau misfolding diseases including AD. The research is exploratory and lays the foundation for future studies into the phenotypic diversity of human Tauopathies and novel therapeutic approaches that utilize homology-based inhibition of Tau fibrillization.