Pathogenesis of Tauopathies

Tau蛋白病的发病机制

基本信息

批准号：
10583338
负责人：
VIRGINIA M LEE
金额：
$ 75.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583338
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Argyrophilic Grain Disease Binding Biochemical Biology Brain Brain Diseases Cell-Free System Clinical Cryoelectron Microscopy Deposition Disease Ensure Experimental Models Frontotemporal Lobar Degenerations Genes Genetic Predisposition to Disease Goals Histologic Human Impairment In Vitro Injections Knockout Mice Lesion Microtubules Modeling Molecular Molecular Conformation Mus Nerve Degeneration Neuroanatomy Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathogenicity Pathologic Pathology Pattern Pick Disease of the Brain Procedures Process Progressive Supranuclear Palsy Property Protein Isoforms Proteins Recombinants Research Risk Factors Role Senile Plaques Susceptibility Gene Tauopathies Testing Therapeutic Toxic effect Transgenic Mice Transportation Wild Type Mouse comorbidity connectome corticobasal degeneration genetic risk factor human model imprint in vivo innovation insight mouse model neuropathology novel overexpression pre-formed fibril risk variant spatiotemporal tau Proteins tau aggregation tau mutation therapeutic development therapeutic target tool transmission process uptake

项目摘要

Aggregated microtubule-associated protein tau (tau) is the common lesion of a group of neurodegenerative diseases with heterogeneous clinical and neuropathological manifestations, collectively referred to as tauopathies. In line with the clinical and pathological diversity, pathological tau aggregates are biologically potent to induce normal tau into aggregations in a strain-dependent manner, suggesting an underlying mechanism of disease-specific tau pathogenesis. The long-term goal of the study is to elucidate the mechanism(s) of the strain-dependent tau transmission and search for therapeutic targets to inhibit the transmission procedure. The central hypothesis is that the imprinted properties of tau strain impair neuron biology via transmission activities. Our rationale is that understanding the mechanism by which tau strains differentially transmit will facilitate the development of therapeutic targets to selectively and efficiently treat different forms of tauopathy by inhibiting the critical transmission steps in tau pathogenesis. Our specific aims are to test the following hypotheses: (Aim 1) amyloid β plaques pathology interact with different forms of tau pathology and modulate of tau transmission; (Aim 2) the conversion of pathological conformations is the molecular basis of tau strain-dependent pathogenicity; (Aim 3) novel genes modulating tau transmission can be targeted as therapeutic strategies for tauopathy. This contribution is significant since the study will elucidate the molecular basis of the diversity of tauopathy and provide specific strategies to treat the diseases. The proposed research is innovative because we will use novel models of tauopathy to spatiotemporally investigate the mechanism of tau transmission and search for potential therapeutic targets with a high degree of disease relevance.

聚集的微管相关蛋白 tau (tau) 是一组具有异质临床和神经病理学表现的神经退行性疾病的常见病变，统称为 tau 病。与临床和病理多样性一致，病理性 tau 聚集体具有诱导正常的生物学作用。 tau 以菌株依赖性方式聚集，表明疾病特异性 tau 发病机制的潜在机制。阐明应变依赖性 tau 传递的机制并寻找抑制传递过程的治疗靶点。我们的基本原理是，tau 应变的印记特性会通过传递活动损害神经元生物学。哪些 tau 菌株差异传播将有助于开发治疗靶点，通过抑制 tau 发病机制中的关键传播步骤来选择性、有效地治疗不同形式的 tau 病。 1) β 淀粉样斑块病理学与不同形式的 tau 病理学相互作用并调节 tau 传播；(目标 2) 病理构象的转换是 tau 菌株依赖性致病性的分子基础；(目标 3) 调节 tau 传播的新基因可以是作为 tau 蛋白病的治疗策略，这一贡献意义重大，因为该研究将阐明 tau 蛋白病多样性的分子基础，并提供治疗这些疾病的具体策略。之所以具有创新性，是因为我们将使用新颖的 tau 蛋白病模型来研究 tau 蛋白传播的时空机制，并寻找与疾病高度相关的潜在治疗靶点。