Hyperphosphorylated tau aggregation kit to identify tauopathy risk factor

项目总结 Tau病是一组神经退行性疾病，具有tau蛋白的共同病理特征。 在中枢神经系统中。最突出的肌萎缩症是阿尔茨海默病(AD)，它会影响 近600万美国人和全球3000多万人。其他紧张症包括 额颞叶变性伴tau、Pick病、进行性核上性麻痹和慢性 创伤性脑病。肌萎缩侧索硬化症患者认知功能和其他功能进行性下降 神经功能。临床表现与神经元的时空分布有关。 异常磷酸化tau(p-tau)的胶质包涵体。动物和细胞研究表明，可溶性的， 寡聚体p-tau对细胞有毒性，并可通过使病理性tau核化而在细胞间传播。 以类似普里恩的方式聚集。因此，抑制或增强聚集的分子和 P-tau的细胞毒性分别是潜在的治疗药物和危险因素。然而，以tau为中心的药物 发现没有取得成果，主要是因为缺乏可靠和简单的合成系统 病理上相关的p-tau。在第一阶段STTR拨款(1R41AG057274)过程中，我们使用 PIMAX系统合成四种具有高度相关核心磷酸化模式的p-tau亚型 这种疾病。我们开发了p-tau聚集的动力学分析方法和基于细胞的细胞毒性分析方法。 是p-tau的。重要的是，我们进行了化学文库筛选，确定了p-tau聚集 以前被认为与痴呆症和阿尔茨海默病有关的抑制剂和增强剂。这些 取得的成就达到并超过了最初第一阶段项目中概述的里程碑。的目标是 目前的第二阶段SBIR项目是开发检测试剂盒，以支持识别治疗方法和风险 包括阿尔茨海默氏症在内的肌萎缩侧索硬化症的因素。此外，利用我们在体内合成的细胞毒性p-tau 设施，我们将培养识别p-tau致病表位的抗体。如果成功，这将导致 早期诊断试剂的发展，甚至是新的对症抗体疗法。通过集成 来自产业界和学术界的团队的互补和协同专业知识，这个SBIR项目将具有 对阿尔茨海默病和其他牛皮病的药物开发、预防和诊断产生了坚实的影响。

PROJECT SUMMARY Tauopathies are a group of neurodegenerative disorders sharing the common pathology of the tau protein in the central nervous system. The most prominent tauopathy is Alzheimer’s disease (AD) that affects nearly 6 million Americans and more than 30 million people worldwide. Additional tauopathies include frontotemporal lobar degeneration with tau, Pick’s disease, progressive supranuclear palsy, and chronic traumatic encephalopathy. Tauopathy patients suffer from progressive decline of cognitive and other neurological functions. Clinical manifestations correlate with the spatiotemporal distribution of neuronal and glial inclusions of abnormally phosphorylated tau (p-tau). Animal and cell studies demonstrated that soluble, oligomeric p-tau are toxic to cells, and can transmit between cells by nucleating the pathological tau aggregation in a prion-like fashion. Accordingly, molecules that inhibit or enhance the aggregation and cytotoxicity of p-tau are potential therapeutics and risk factors, respectively. However, tau-centric drug discovery has not come to fruition due primarily to the lack of a reliable and simple system for the synthesis of pathologically relevant p-tau. During the course of a Phase I STTR grant (1R41AG057274), we used the PIMAX system to synthesize four isoforms of p-tau bearing a core phosphorylation pattern highly relevant to the disease. We developed kinetics assays for p-tau aggregation, and cell-based assays for the cytotoxicity of p-tau. Importantly, we conducted a chemical library screen that identified both p-tau aggregation inhibitors and enhancers that had been linked previously to dementia and Alzheimer's disease. These achievements met and exceeded the milestones outlined in the original Phase I project. The goal of the current Phase II SBIR project is to develop assay kits to support the identification of therapeutics and risk factor of tauopathies, including Alzheimer's disease. In addition, using the cytotoxic p-tau synthesized in our facilities, we will raise antibodies recognizing the pathogenic epitope of p-tau. If successful, this will lead to the development of early diagnostic reagents and even novel tauopathy antibody therapies. By integrating complementary and synergic expertise of teams from industry and academia, this SBIR project will have solid impact on drug development, prevention, and diagnosis of Alzheimer’s disease and other tauopathies.