Microglial and macrophage potassium channels as regulators of neuroinflammation in Alzheimer's Disease

小胶质细胞和巨噬细胞钾通道作为阿尔茨海默病神经炎症的调节因子

• 批准号: 9977290
• 负责人: Srikant Rangaraju
• 金额: $ 18.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977290
• 关键词: Abeta clearance; Address; Adopted; Adult; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Basic Science; Bioinformatics; Biological Assay; Biological Response Modifiers; Biology; Biometry; Blood; Brain; Calcium Signaling; Cell model; Cells; Chemotaxis; Chronic; Clinical; Clinical Research; Cognitive deficits; Core Facility; Data; Dementia; Dependence; Deposition; Development; Disease; Disease Progression; Endotoxins; Environment; Equilibrium; Flow Cytometry; Funding; Future; Genes; Genetic Transcription; Gliosis; Goals; Grant; Health; Health Expenditures; Hour; Human; Immune; Immune response; Immune signaling; Immunoassay; Immunology; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Institution; Intraperitoneal Injections; Ion Channel; Journals; K-Series Research Career Programs; Knowledge; Laboratory Research; Lead; Measures; Mediating; Mentors; Mentorship; Methods; Microglia; Mononuclear; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurologist; Neurology; Neurons; Neurosciences; Neurosciences Research; Nitric Oxide; Outcome; Pathogenesis; Pathway Analysis; Pattern; Peptide Synthesis; Peripheral; Persons; Phagocytes; Phagocytosis; Physicians; Placebos; Potassium; Potassium Channel; Production; Proteins; Proteomics; Publications; Reactive Oxygen Species; Records; Regulation; Research; Research Methodology; Research Personnel; Research Proposals; Research Technics; Research Training; Resources; Rodent; Role; Scientist; Senile Plaques; Signal Transduction; Systems Biology; Teacher Professional Development; Testing; Therapeutic; Time; Toxic effect; Training; Translating; Translational Research; United States National Institutes of Health; Universities; Work; Writing; abeta accumulation; analytical method; brain cell; career; career development; cellular imaging; channel blockers; chemokine; conditioned fear; cytokine; differential expression; immune function; immunoregulation; in vitro Model; in vivo Model; inhibitor/antagonist; insight; leadership development; macrophage; meetings; monocyte; morris water maze; mouse model; neurobehavioral; neuroinflammation; neuron loss; neuropathology; neurotoxic; new therapeutic target; novel; novel therapeutics; patch clamp; peripheral blood; post-doctoral training; programs; recruit; response; responsible research conduct; skills; tool; translational neuroscience; treatment trial; voltage

Project summary/Abstract Candidate I am a board-certified neurologist committed to a career in health-oriented basic and translational research. I have research expertise in ion channel biology and immunology, clinical research methods and clinical neurology. My long-term goal is to establish myself as a successful independent physician-scientist in neuroinflammation and translational neuroscience. To achieve this goal and facilitate my transition to independence, I seek 5 years of mentored training through a NIH K08 career development award to fill gaps in my research training, establish a network of future research collaborators, build my publication record and grant-writing skills and pursue training in leadership and faculty development. Environment The training and mentoring environment at Emory is ideally suited for my career development. My mentorship committee at Emory University is comprised of experts and independent scientists in the fields of neurodegeneration (Dr. Allan Levey), neuroinflammation (Dr. Malu Tansey) and proteomics/systems biology (Dr. Nicholas Seyfried), each with exemplary records of NIH and non-federal funding, leading successful and productive research groups and training post-doctoral and physician-scientist trainees. My mentors and their research groups will provide me with hands-on training in (1) Animal models of neurodegeneration as tools to facilitate translational research, (2) Functional assays of microglia and macrophages, immune signaling, immunoassays, glial biology, and (3) Proteomics, bioinformatics and systems biology. I will receive research mentorship through weekly and monthly interactions and direct oversight of my research progress, presentations at journal clubs, seminars and presentations at local and national meetings. I will also receive formal coursework in glial biology, immunology, advanced methods in neuroscience research, bioinformatics, R programing, systems biology (WeiGhted Correlation Network Analysis) and in the responsible conduct of research (>12 credit hours and in-person training that fulfils NIH requirements) at Emory University. A team of intra- and extra-mural contributors with expertise in systems biology, peptide synthesis, potassium channel biology and biostatistics will also guide the proposed research. Emory University is a large academic institution with Neuroscience and Neurology receiving one of highest research funding from the NIH (9th in the US). The Emory Center for Neurodegenerative Diseases (CND) is a collaborative and cross-disciplinary research environment with shared laboratory and research resources supported by NIH-funded research core facilities in neuropathology, proteomics, multiplexed immunoassays, flow cytometry, cell imaging and rodent neurobehavioral methods. Research Disease-modifying therapies are lacking for Alzheimer’s disease (AD), the most common cause of dementia worldwide. Immune responses mediated by mononuclear phagocytes (MPs) in AD and other neurodegenerative diseases are increasingly recognized to influence neurodegeneration through pro- inflammatory (disease-promoting) and anti-inflammatory (protective) mechanisms. Selective inhibitors of pro- inflammatory functions that spare and/or promote anti-inflammatory effects may lead to development of novel disease-modifying therapies for AD as well as other neurodegenerative diseases. Potassium channels expressed by MPs in the brain are key regulators of immune functions and our preliminary data suggest that pro-inflammatory MP functions are regulated by Kv1.3 potassium channels while anti-inflammatory MP functions are regulated by a different K channel called Kir2.1. In this proposal, we will first determine the functional importance of Kv1.3 and Kir2.1 channels in pro- and anti-inflammatory MP functions including reactive oxygen species production, cytokine/chemokine production in-vitro; and will investigate the down- stream signaling and transcriptional effects of Kv1.3 and Kir2.1 channel blockade in MPs (Aim 1). Next, we will determine expression patterns of these two potassium channels in peripheral blood monocyte-derived macrophages and microglia isolated from the mouse AD brain and will test whether these channels regulate the ability of peripherally derived MPs to enter the brain in a mouse model of AD pathology (Aim 2). Lastly, we will perform initial studies of chronic blockade of Kv1.3 and Kir2.1 channels using novel highly-selective and potent blockers as therapeutic strategies to mitigate neurodegeneration and cognitive deficits in the 5xFAD mouse model of AD (Aim 3). The results of this work will provide novel insights into microglial and macrophage biology, immune regulation in neurodegenerative diseases and potentially identify novel therapeutic strategies that can modify disease progression in AD. The data generated from these research aims will also advance the candidate’s career development and will lead to future independent investigator (R01) grants and future collaborative research across the spectrum of neurodegenerative and neuro-inflammatory diseases.

项目摘要/摘要 候选人 我是一名经过董事会认证的神经科医生，致力于从事以健康为导向的基础和翻译研究的职业。我 具有离子渠道生物学和免疫学，临床研究方法和临床方面的研究专业知识 神经病学。我的长期目标是将自己确立为成功的独立身体科学家 神经炎症和转化神经科学。实现这一目标并促进我向 独立性，我通过NIH K08职业发展奖寻求5年的指导培训，以填补空白 我的研究培训，建立一个未来研究合作者网络，建立我的出版记录和 在领导力和教师发展方面的赠款技巧和实践培训。 环境 Emory的培训和心理环境非常适合我的职业发展。我的精神训练 埃默里大学的委员会由该领域的专家和独立科学家组成 神经变性（Allan Levey博士），神经炎症（Malu Tansey博士）和蛋白质组学/系统生物学 （尼古拉斯·塞弗里德（Nicholas Seyfried）博士），每个人都有NIH和非联邦资金的典范记录，领导了成功和 生产性研究小组和培训博士后和身体科学的学员。我的导师和他们的 研究小组将为我提供（1）神经退行性动物模型的动手培训作为工具 促进翻译研究，（2）小胶质细胞和巨噬细胞的功能评估，免疫信号传导， 免疫测定，神经胶质生物学和（3）蛋白质组学，生物信息学和系统生物学。我会得到研究 通过每周和每月互动以及直接监督我的研究进度的遗产， 在期刊俱乐部，半小伙子和演讲中的演讲。我也会收到 神经胶质生物学，免疫学，神经科学研究高级方法的正式课程，生物信息学， R编程，系统生物学（加权相关网络分析）以及负责任的行为 埃默里大学（Emory University）的研究（> 12个学时和满足NIH要求的面对面培训）。一个团队 具有系统生物学专业知识，肽合成，钾通道方面的专业知识和壁外贡献者 生物学和生物统计学还将指导拟议的研究。埃默里大学是一个大型学术机构 神经科学和神经病学获得了NIH的最高研究资金之一（美国第9位）。这 Emory神经退行性疾病中心（CND）是一项协作和跨学科研究 由NIH资助的研究核心设施支持的共享实验室和研究资源的环境 在神经病理学，蛋白质组学，多重免疫测定，流式细胞术，细胞成像和啮齿动物 神经行为方法。 研究 阿尔茨海默氏病（AD）缺乏改良疾病的疗法，这是痴呆症的最常见原因 全世界。 AD和其他AD中的单核吞噬细胞（MP）介导的免疫反应 神经退行性疾病越来越被认识到通过促进影响神经退行性的 炎症（促进疾病）和抗炎（保护性）机制。选择性抑制剂 避免和/或促进抗炎作用的炎症功能可能会导致新颖的发展 疾病改良的AD以及其他神经退行性疾病。钾通道 大脑中由国会议员表达的是免疫功能的关键调节剂，我们的初步数据表明 促炎的MP功能由KV1.3钾通道调节，而抗炎MP 功能由称为KIR2.1的不同K通道调节。在此提案中，我们将首先确定 KV1.3和KIR2.1通道在促炎和抗炎MP功能中的功能重要性包括 活性氧的产生，细胞因子/趋化因子的产生；并将调查唐 MPS中KV1.3和KIR2.1通道阻滞的流信号传导和转录效应（AIM 1）。接下来，我们会的 确定外周血单核细胞中这两个钾通道的表达模式 巨噬细胞和从小鼠广告大脑中分离出的小胶质细胞，并将测试这些通道是否调节 外围派生的MPS以AD病理的小鼠模型进入大脑的能力（AIM 2）。最后，我们 将使用新型的高度选择性和 有效的阻滞剂作为减轻5xFAD神经变性和认知防御的治疗策略 AD的鼠标模型（AIM 3）。这项工作的结果将为小胶质细胞和巨噬细胞提供新的见解 生物学，神经退行性疾病中的免疫调节，并可能识别新的治疗策略 这可以改变AD中的疾病进展。这些研究目的产生的数据也将推动 候选人的职业发展，并将导致未来的独立调查员（R01）赠款和未来 跨神经退行性和神经炎症疾病的合作研究。

项目成果

C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19.

• DOI: 10.1371/journal.pone.0242400
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sharifpour M;Rangaraju S;Liu M;Alabyad D;Nahab FB;Creel-Bulos CM;Jabaley CS;Emory COVID-19 Quality & Clinical Research Collaborative
• 通讯作者: Emory COVID-19 Quality & Clinical Research Collaborative