Role of 14-3-3θ in Environmental Toxicant Exposure and Neuroinflammation in Synucleinopathies

14-3-3α 在环境有毒物质暴露和突触核蛋白病神经炎症中的作用

• 批准号: 10605908
• 负责人: William J Stone
• 金额: $ 4.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605908
• 关键词: Acceleration; Area; Attenuated; Biological Assay; Brain; Cell Death; Cells; Clinical; Communication; Data; Dementia with Lewy Bodies; Dependovirus; Development; Disease; Doctor of Philosophy; Environment; Evaluation; Event; Exposure to; Familiarity; Foundations; Functional disorder; Future; Goals; Grant; Human; Immune; In Vitro; Industrialization; Interferon Type II; Knock-in; Knowledge; LRRK2 gene; Laboratories; Lewy Bodies; Lewy body pathology; Lewy neurites; Literature; Manuscripts; Mediating; Mediator; Mentors; Microglia; Modeling; Molecular; Movement Disorders; Mus; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neurology; Neurons; Neurosciences; Neurosciences Research; Neurotoxins; Oral; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Phosphorylation; Physicians; Prevalence; Process; Protein Isoforms; Proteins; Rattus; Reporting; Research; Research Proposals; Rodent; Role; Scientist; Serine; Severities; Signal Induction; Solid; Solvents; Substantia nigra structure; Tamoxifen; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Training; Translational Research; Trichloroethylene; United States National Institutes of Health; Variant; Wild Type Mouse; Work; Writing; aged; alpha synuclein; career; career development; clinical application; disorder risk; dopaminergic neuron; experience; genetic manipulation; glial activation; ground water; immunoreactivity; in vivo; in vivo Model; mimetics; mutant; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; nigrostriatal degeneration; overexpression; pars compacta; precision medicine; prevent; research and development; response; responsible research conduct; skill acquisition; skills; synucleinopathy; therapeutic gene; therapy development; translational approach; vector; virtual; volatile organic compound

Project Summary The purpose of this NIH F31 application is to obtain support for the PI, W. Jay Stone, for mentored research and career development activities within his MD/PhD degree training that will strengthen his potential to become a successful physician scientist. The project goal is to develop skills in neuroscience that will allow the PI to study key proteins involved in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB), using laboratory assays foundational to research in neuroscience. The primary objective of this research proposal is to investigate the role of 14-3-3θ phosphorylation in the context of environmental toxicant exposure and the neuroinflammatory response associated with synucleinopathies. Work from the lab of Dr. Talene Yacoubian, sponsor of the PI, has established 14-3-3θ as a key mediator of pathologic mechanisms by which neurons degenerate in models of PD and DLB, and serves as a potential target for disease modifying therapy. Furthermore, our lab has revealed that phosphorylation of 14-3-3θ at serine residue 232 (pS232) modulates its ability to interact with and prevent the aggregation of α-syn, the critical pathologic protein implicated in PD and DLB. However, the events which lead to aberrant pS232 levels are unclear. This project aims to increase our understanding of the mechanisms that induce pS232 and promote neurodegeneration in two synucleinopathy-associated events: exposure to the environmental toxicant, trichloroethylene (Aim 1) and neuroinflammation (Aim 2). The long-term objective of our research is to better understand the role of 14-3-3θ phosphorylation within synucleinopathies so that subsequent studies can be devised to target 14-3-3θ for developing potential disease-modifying therapeutics. The proposed training plan for Jay Stone is sponsored by his project mentor, Dr. Talene Yacoubian, and co- sponsored by Dr. David Standaert. The overall goal of the training plan is to provide the PI with a solid foundation for a successful career as a physician scientist. A project based both in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that will help Jay develop in three major areas: 1) rigorous neuroscience research in synucleinopathies, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) training in advanced gene therapeutics, and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required to conduct rigorous scientific research in synucleinopathies and advanced neuroscience skills necessary for the PI’s future career as a neurology physician-scientist focused on precision medicine and neurodegenerative diseases.

项目摘要 本NIH F31申请的目的是获得PI，W。杰伊·斯通（Jay Stone），负责指导研究和 在他的MD/PhD学位培训中的职业发展活动，将加强他成为一名 成功的医学科学家该项目的目标是发展神经科学的技能，使PI能够研究 参与突触核蛋白病发病机制的关键蛋白，包括帕金森病（PD）和 路易体痴呆症（DLB），使用神经科学研究基础的实验室分析。的 本研究的主要目的是研究14-3-3θ磷酸化在 环境毒物暴露和与突触核蛋白病相关的神经炎症反应。工作 来自Talene Yacoubian博士（PI的申办者）的实验室，已经确定14-3-3θ是病理性 神经元在PD和DLB模型中退化的机制，并作为疾病的潜在靶点 改良疗法此外，我们的实验室已经揭示了14-3-3θ在丝氨酸残基232处的磷酸化， （pS232）调节其与α-syn相互作用并阻止α-syn聚集的能力，α-syn是关键的病理蛋白质 与PD和DLB有牵连。然而，导致异常pS232水平的事件尚不清楚。这个项目 目的是增加我们对诱导pS232和促进神经退行性变的机制的理解， 两个突触核蛋白病相关事件：暴露于环境毒物三氯乙烯（目标1）， 神经炎症（目的2）。我们研究的长期目标是更好地了解14-3-3θ的作用 突触核蛋白病中的磷酸化，以便随后的研究可以设计为靶向14-3-3θ， 开发潜在的疾病改善疗法。 Jay Stone的拟议培训计划由他的项目导师Talene Yacoubian博士赞助， 由大卫·斯坦德特博士赞助培训计划的总体目标是为PI提供坚实的基础 作为一名成功的医学科学家一个基于翻译方法的项目， 以疾病为导向的发病机制，是任何有抱负的医生科学家的理想培训环境。 包括在培训计划的经验，将有助于周杰伦发展在三个主要领域：1）严格 突触核蛋白病的神经科学研究，包括熟悉现有文献， 对数据进行批判性评估，并进行负责任的研究行为培训; 2）先进基因的培训 治疗学，和3）职业和专业发展，包括赠款和手稿写作，科学 沟通，并将研究成果转化为临床应用。该提案推动了 发展在突触核蛋白病和先进的进行严格的科学研究所需的技能 PI未来作为神经病学医生-科学家的职业生涯所需的神经科学技能，专注于精确度 药物和神经退行性疾病。