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

有效减少来自大脑实质的总tau将减少发育， 零星和家族性AD的进展 （FTD）和其他tauopathies。但是，从大脑降低总tau的途径很差 理解。神经炎症是神经退行性疾病的另一个标志，最近 表明磷酸-TAU病理学的进展是由小胶质细胞驱动的，小胶质细胞激活 形成TAU聚集与脑损伤之间的关键联系。在这里，我们想检验一个新的假设 MyD88（WTTIDM）肽抑制野生型TLR2相互作用结构域的鼻内施用 小胶质细胞炎症（特定目标I）并减少p31S转基因小鼠中的tauopathy（特定AIM II） 通过TLR2。这项尖端R21赠款提案的积极结果将描述 TLR2和Tauopathy并描述WTTIDM肽对TLR2激活状态的选择性靶向还原 缠结病理学，突出发现了一种前瞻性鼻内药物，以减少AD中的tau病理， PSP，FTD和其他Tauopathies。 1