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Hyperphosphorylated tau aggregation kit to identify tauopathy risk factor

过度磷酸化 tau 蛋白聚集试剂盒，用于识别 tau 蛋白病危险因素

基本信息

批准号：
10265535
负责人：
MARIA INES MORANO
金额：
$ 73.45万
依托单位：
CAYMAN CHEMICAL COMPANY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265535
关键词：
Academia Achievement Affect Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis American Animals Antibodies Antibody Therapy Biological Assay CDK5 gene Categories Cell Line Cells Cellular Assay Clinical Complement Dementia Development Diagnosis Diagnostic Reagent Disease Early Diagnosis Enhancers Epitopes Family Frontotemporal Lobar Degenerations Fruit Glycogen Synthase Kinase 3 Goals Grant Impaired cognition Industry Kinetics Link Membrane Potentials Mitochondria Monoclonal Antibodies Nerve Degeneration Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurons Pathogenicity Pathologic Pathology Patients Pattern Phase Phosphorylation Phosphotransferases Pick Disease of the Brain Prevention Progressive Supranuclear Palsy Protein Isoforms Protocols documentation Reagent Regimen Reproducibility Risk Factors Small Business Innovation Research Grant Small Business Technology Transfer Research Solid System Tauopathies Therapeutic Therapeutic Agents Toxic effect Validation abnormally phosphorylated tau base cell killing chronic traumatic encephalopathy commercialization cytotoxic cytotoxicity drug development drug discovery hyperphosphorylated tau inhibitor/antagonist novel prion-like screening small molecule small molecule libraries spatiotemporal tau Proteins tau aggregation tau-1

项目摘要

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.

项目概要 tau 蛋白病是一组具有 tau 蛋白共同病理学特征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)，它影响近 600 万美国人和全球超过 3000 万人。其他 tau蛋白病包括额颞叶变性伴 tau 蛋白、皮克氏病、进行性核上性麻痹和慢性外伤性脑病。 tau蛋白病患者的认知能力和其他能力逐渐下降神经功能。临床表现与神经元和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，可溶性、寡聚 p-tau 对细胞有毒，可以通过使病理性 tau 成核而在细胞之间传播以类似朊病毒的方式聚集。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方法和危险因素。然而，以 tau 为中心的药物主要由于缺乏可靠且简单的合成系统，这一发现尚未实现病理相关的p-tau。在第一阶段 STTR 拨款 (1R41AG057274) 的过程中，我们使用了 PIMAX 系统可合成 4 种 p-tau 亚型，其核心磷酸化模式与这种疾病。我们开发了 p-tau 聚集的动力学测定以及基于细胞的细胞毒性测定 p-tau。重要的是，我们进行了化学库筛选，鉴定了 p-tau 聚集以前曾与痴呆和阿尔茨海默病有关的抑制剂和增强剂。这些所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。的目标当前的 II 期 SBIR 项目是开发检测试剂盒，以支持治疗方法和风险的识别 tau蛋白病的因素，包括阿尔茨海默病。此外，使用我们合成的细胞毒性 p-tau 设施，我们将产生识别 p-tau 致病表位的抗体。如果成功的话，这将导致早期诊断试剂甚至新型 tau 蛋白病抗体疗法的开发。通过整合该 SBIR 项目将结合工业界和学术界团队的互补和协同专业知识对阿尔茨海默病和其他 tau蛋白病的药物开发、预防和诊断产生了重大影响。