Investigation of TRIM9 in cell shape change in the aging brain

TRIM9 在衰老大脑细胞形状变化中的研究

基本信息

批准号：
10121328
负责人：
Stephanie Gupton
金额：
$ 19.94万
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：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10121328
关键词：
Actins Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Anti-Inflammatory Agents Area Asses Autopsy Axon Biological Assay Biotin Brain Cell Shape Cells Characteristics Collaborations DCC gene Data Dendritic Spines Development Disease Progression Exhibits Functional disorder Funding Future Genes Goals Growth Cones Health Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Investigation Ischemic Stroke Learning Lewy Body Dementia Ligation Mass Spectrum Analysis Melanoma Cell Membrane Memory Morphogenesis Morphology Mus National Institute of General Medical Sciences Nervous system structure Neurons Ontology Paraneoplastic Cerebellar Degeneration Parents Parkinson&apos s Dementia Pathology Patients Physiology Play Polymerase Post-Translational Protein Processing Predisposition Protein Isoforms Proteins Regulation Research Role Shapes Synapses Ubiquitination Wild Type Mouse Work aging brain base density experimental study follow-up interest mouse model netrin receptor neuroinflammation novel novel marker overexpression paralogous gene postsynaptic response 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 nine 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. This includes not only changes in developmentally relevant stages such as growth cone morphology, and axonal and dendritic branching, but later morphogenetic stages with synaptic function relevance, such as dendritic spine density. 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. Here, we propose to expand our investigation into how TRIM9 specifically affects the shape and function of the aging neuron, and susceptibility to AD.

项目概要在过去的九年里，我的实验室一直专注于大脑富集 E3 泛素的功能连接酶 TRIM9。我们对 TRIM9 的兴趣源于我们对直接相互作用的识别 TRIM9 和肌动蛋白聚合酶 VASP、胞吐突触 t-SNARE SNAP25 和 netrin 受体 DCC。这使我们推测 TRIM9 协调细胞骨架和 netrin 期间的膜重塑引发细胞形状变化。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。这不仅包括发育方面的变化相关阶段，例如生长锥形态、轴突和树突分支，但后来与突触功能相关的形态发生阶段，例如树突棘密度。一些一系列证据表明 TRIM9 可能继续在健康和功能中发挥关键作用老化的神经元。首先，TRIM9在神经系统中的富集持续到成人并且是在人类帕金森病和路易痴呆症患者的大脑中受到抑制尸体。我们的工作表明，小鼠 Trim9 的缺失会导致显着的认知能力损害，特别是空间学习和记忆方面的损害。 Trim9缺陷小鼠表现出增加神经炎症，而增加 TRIM9 表达在以下情况下发挥神经保护作用：缺血性中风。最后，TRIM9 是副肿瘤性小脑变性的新标记物。在这里，我们建议扩大我们对 TRIM9 如何具体影响形状和老化神经元的功能和 AD 的易感性。