Exploring The Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer's Disease

探索大脑富含 E3 泛素连接酶 TRIM9 在阿尔茨海默病中的作用

基本信息

批准号：
10467201
负责人：
Stephanie Gupton
金额：
$ 42.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467201
关键词：
Actins Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Anti-Inflammatory Agents Area Autopsy Axon Biological Assay Biotin Brain Cells Characteristics Cognitive Collaborations DCC gene Data Dementia with Lewy Bodies Dendritic Spines Development Disease Progression Exhibits Functional disorder Future Genes Golgi Apparatus Growth Cones Health Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Investigation Ischemic Stroke Label Learning Ligation Link Mass Spectrum Analysis Membrane Memory Morphogenesis Morphology Mus Nerve Degeneration Nervous system structure Neurons Ontology Paraneoplastic Cerebellar Degeneration Parkinson&apos s Dementia Pathology Patients Physiology Play Polymerase Predisposition Proteins Proteome Regulation Research Role Shapes Stains Synapses Testing Time Ubiquitination Wild Type Mouse Work aged base brain tissue density experimental study follow-up interest mouse model multicatalytic endopeptidase complex netrin receptor neuroinflammation novel novel marker overexpression postsynaptic protein aggregation protein biomarkers synaptic function target SNARE proteins tau Proteins tau aggregation tau-1 ubiquitin-protein ligase vasodilator-stimulated phosphoprotein

项目摘要

PROJECT SUMMARY Over the past ten years, my lab has focused on the function of the brain enriched E3 ubiquitin ligase TRIM9. Our interest in TRIM9 originated from our identification of direct interactions between TRIM9 and the actin polymerase VASP, the exocytic synaptic t-SNARE SNAP25 and the netrin receptor DCC. This led us to hypothesize that TRIM9 coordinated cytoskeletal and membrane remodeling during netrin triggered cellular shape change. Our work has shown that TRIM9 regulates cytoskeletal dynamics and membrane remodeling during several critical stages of morphogenesis of developing neurons and that deletion of Trim9 results in a complete loss of spatial learning and memory. Several lines of evidence suggest that TRIM9 may continue to play a critical role in the health and function of the aging neuron. First, TRIM9 enrichment in nervous system continues into adult and is repressed in the brains of human patients with Parkinson’s disease and dementia with Lewy bodies. Our work has shown that deletion of murine Trim9 results in dramatic cognitive impairment, specifically in spatial learning and memory. Trim9-deficient mice exhibit increased neuroinflammation, whereas increasing TRIM9 expression plays neuroprotective roles following ischemic stroke. Finally, TRIM9 is a novel marker for paraneoplastic cerebellar degeneration. Our recent proximity labeling experiments identified a candidate TRIM9 interactome, which contained several proteins implicated in synaptic function and Alzheimer’s disease. Preliminary data indicated TRIM9 affects dendritic spine density. Here, we propose to expand our investigations into how TRIM9 specifically affects the shape and function of the aging neuron, and susceptibility to AD.

项目摘要在过去的十年中，我的实验室专注于大脑富集E3的功能连接酶Trim9。我们对TRIM9的兴趣来自我们对直接互动的识别在TRIM9和肌动蛋白聚合酶VASP之间 Netrin受体DCC。这导致我们假设TRIM9协调的细胞骨架和 Netrin期间的膜重塑触发了细胞形状的变化。我们的工作表明 TRIM9在几个关键阶段调节细胞骨架动力学和膜重塑发育神经元的形态发生以及TRIM9的缺失导致完全丧失空间学习和记忆。有几条证据表明TRIM9可能会继续播放在衰老神经元的健康和功能中的关键作用。首先，trim9富集紧张系统持续成人，并反映在帕金森氏症患者的大脑中 Lewy身体的疾病和痴呆症。我们的工作表明，删除鼠Trim9结果在戏剧性的认知障碍中，特别是在空间学习和记忆中。 TRIM9缺陷小鼠暴露的神经炎症增加，而TRIM9表达播放增加缺血性中风后神经保护作用。最后，Trim9是一个新颖的标记副塑性小脑变性。我们最近的接近标签实验确定了候选Trim9 Interactome，其中包含在突触功能中实现的几种蛋白质和阿尔茨海默氏病。初步数据表明TRIM9会影响树突状脊柱密度。这里，我们建议将调查扩展到TRIM9如何专门影响形状和衰老神经元的功能以及对AD的敏感性。