Hyperphosphorylated tau aggregation kit to identify tauopathy risk factor

项目摘要 tau蛋白病是一组具有tau蛋白共同病理学的神经退行性疾病 在中枢神经系统中。最突出的tau蛋白病是阿尔茨海默病（AD），其影响 近600万美国人和全球3000多万人。其他tau蛋白病包括 额颞叶变性伴tau蛋白、皮克病、进行性核上性麻痹和慢性 创伤性脑病Tauopathy患者患有认知和其他功能的进行性下降， 神经功能。临床表现与神经元的时空分布相关， 异常磷酸化tau（p-tau）的神经胶质内含物。动物和细胞研究表明， 寡聚体p-tau对细胞是有毒的，并且可以通过使病理性tau成核而在细胞之间传递 以朊病毒样的方式聚集。因此，抑制或增强聚集并 p-tau细胞毒性分别是潜在的治疗剂和危险因素。然而，tau中心药物 这一发现尚未取得成果，主要是由于缺乏可靠和简单的合成系统 病理相关的p-tau蛋白在第一阶段STTR赠款（1 R41 AG 057274）的过程中，我们使用了 PIMAX系统合成四种p-tau亚型，其具有与以下高度相关的核心磷酸化模式： 这种疾病我们开发了p-tau聚集的动力学测定和细胞毒性的基于细胞的测定。 的P-tau。重要的是，我们进行了一个化学文库筛选， 抑制剂和增强剂，以前与痴呆症和阿尔茨海默病有关。这些 这些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 目前的SBIR第二阶段项目是开发检测试剂盒，以支持治疗和风险的识别 tau蛋白病的因子，包括阿尔茨海默病。此外，使用我们合成的细胞毒性p-tau， 我们将提高识别p-tau致病表位的抗体。如果成功，这将导致 开发早期诊断试剂，甚至开发新型tau蛋白病抗体疗法。通过整合 来自工业界和学术界的团队的互补和协同专业知识，这个SBIR项目将有 对阿尔茨海默病和其他tau蛋白病的药物开发、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.