DnaJB6 as a novel regulator of tau

DnaJB6 作为 tau 蛋白的新型调节剂

基本信息

批准号：
10677195
负责人：
Abigail Esquivel
金额：
$ 3.79万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2023-08-14 至 2026-08-13
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677195
关键词：
Affect Alzheimer&apos s Disease Amyloid Behavior Behavioral Bilateral Biochemical Process Biological Assay Biology Biosensor Brain Cause of Death Cell model Cells Clinical assessments Cognition Cognitive Cognitive deficits Complement Data Dementia Deposition Development Disease Disease Progression Family Family member Fluorescence Fluorescence Resonance Energy Transfer Genes Goals Health Hippocampus Histologic Huntington gene Impaired cognition Individual Knowledge Label Link Literature Molecular Molecular Chaperones Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Outcome Pathogenesis Pathologic Pathology Pathway interactions Proteins Proteomics Recombinants Regulation Research Role Severities Surface Plasmon Resonance Tauopathies Testing Therapeutic Toxic effect Transgenic Mice Translating Work aged antagonist brain health brain tissue cognitive function effective therapy experimental study heat-shock proteins 40 improved in vitro Assay in vivo inhibitor interest knock-down member mouse model neuron loss neurotoxicity novel novel therapeutics overexpression polyglutamate prevent protective pathway protein TDP-43 protein aggregation protein protein interaction resilience screening small hairpin RNA synuclein tau Proteins tau aggregation therapeutic development therapeutically effective virtual

项目摘要

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal loss driven by deposits of pathological tau. Therefore, identifying and targeting potent regulators of tau is crucial in developing effective therapeutic strategies. My exciting preliminary data show DnaJB6 overexpression decreases tau levels in HEK293T cells more than 50%, and in parallel, knockdown of DnaJB6 results in a 2-fold increase of tau. This suggests that DnaJB6 may regulate tau levels, however, the nature of this relationship has not yet been investigated. In this proposal, I will test the hypothesis that DnaJB6 can prevent tau accumulation through direct and indirect mechanisms. In Aim 1, I will test this through assessing protein-protein interaction dynamics between DnaJB6 and tau with recombinant in vitro assays, including Thioflavin T fluorescence and Surface Plasmon Resonance. A targeted proteomic approach will be used to identify direct and proximal connections between DnaJB6 and tau in primary neurons. In Aim 2, we will use PS19 and non-transgenic mice to assess the associated behavioral and molecular changes that result from DnaJB6 overexpression in the brain. Successful completion of these studies will provide crucial information regarding DnaJB6 biology, direct and indirect effects of DnaJB6 on tau, and how regulation of DnaJB6 affects behavioral and molecular changes in the tauopathic brain.

抽象的阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是由以下因素引起的神经元损失：因此，识别和靶向 tau 的有效调节因子对于开发至关重要。我令人兴奋的初步数据显示 DnaJB6 过度表达会降低 tau 蛋白的水平。 HEK293T 细胞中的水平超过 50%，同时，DnaJB6 的敲低会导致 DnaJB6 的水平增加 2 倍。这表明 DnaJB6 可能调节 tau 水平，但这种关系的性质尚未确定。在这个提案中，我将测试 DnaJB6 可以通过以下方式阻止 tau 积累的假设。在目标 1 中，我将通过评估蛋白质-蛋白质相互作用动力学来测试这一点。通过重组体外测定（包括硫磺素 T 荧光和表面）在 DnaJB6 和 tau 之间进行比较等离子共振将用于识别直接和近端连接。在目标 2 中，我们将使用 PS19 和非转基因小鼠来评估原代神经元中 DnaJB6 和 tau 之间的差异。大脑中 DnaJB6 过度表达导致的相关行为和分子变化。这些研究的成功完成将提供有关 DnaJB6 生物学、直接和 DnaJB6 对 tau 蛋白的间接影响，以及 DnaJB6 的调节如何影响行为和分子变化 tau蛋白病的大脑。