Intranasal TIDM peptide for tauopathy

用于治疗 tau 蛋白病的鼻内 TIDM 肽

• 批准号: 10059127
• 负责人: KALIPADA PAHAN
• 金额: $ 39.25万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059127
• 关键词: Alzheimer' s Disease; Applications Grants; Bacteria; Binding; Brain; Brain Injuries; Cells; Development; Engineering; Flagellin; Frontotemporal Dementia; Inflammation; Innate Immune System; Intranasal Administration; Link; Microglia; Monitor; Mus; Mutate; Natural Immunity; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Pathologic; Pathology; Pathway interactions; Peptides; Progressive Supranuclear Palsy; Specificity; TLR2 gene; Tauopathies; Testing; Therapeutic; Toll-like receptors; Transgenic Mice; Viral; Virus; adaptive immunity; brain parenchyma; cell type; effective therapy; familial Alzheimer disease; hyperphosphorylated tau; inhibitor/antagonist; neuroinflammation; novel; prospective; tau Proteins; tau aggregation; tau-1

Effective reduction of aggregated tau from the brain parenchyma is expected to reduce the development and progression of both sporadic and familial AD, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and other tauopathies. However, pathways for lowering aggregated tau from the brain are poorly understood. Neuroinflammation is another hallmark of neurodegenerative disorders and recently it has been shown that the progression of phospho-tau pathology is driven by microglia and that microglial activation forms the crucial link between tau aggregation and brain damage. Here, we want to test a novel hypothesis that intranasal administration of wild type TLR2-interacting domain of MyD88 (wtTIDM) peptide suppresses microglial inflammation (Specific aim I) and decreases tauopathy (Specific aim II) in P301S transgenic mice via TLR2. A positive outcome of this cutting-edge R21 grant proposal will delineate a new crosstalk between TLR2 and tauopathy and describe if selective targeting of activated status of TLR2 by wtTIDM peptide reduces tangle pathology, highlighting the discovery of a prospective intranasal agent to reduce tau pathology in AD, PSP, FTD, and other tauopathies. 1

从脑实质中有效减少聚集的tau预期会减少脑胶质瘤的发生和发展。 散发性和家族性AD的进展、进行性核上性麻痹（PSP）、额颞叶痴呆 (FTD)和其他Tau病。然而，从大脑中降低聚集的tau蛋白的途径很差， 明白神经炎症是神经退行性疾病的另一个标志，最近， 显示磷酸化tau病理学的进展是由小胶质细胞驱动的， 形成了tau蛋白聚集和脑损伤之间的关键联系。在这里，我们想测试一个新的假设， 鼻内施用MyD88野生型TLR2相互作用结构域（wtTIDM）肽抑制 P301S转基因小鼠中的小胶质细胞炎症（具体目的I）和减少tau蛋白病（具体目的II） 通过TLR2。这项尖端的R21拨款提案的积极成果将描绘出一个新的串扰， TLR2和tau蛋白病，并描述通过wtTIDM肽选择性靶向TLR2的活化状态是否降低 缠结病理学，突出了一种减少AD中tau病理学的前瞻性鼻内药物的发现， PSP、FTD和其他tau蛋白病。 1