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.

项目概要/摘要 候选 我是一名委员会认证的神经学家，致力于健康导向的基础和转化研究。我 具有离子通道生物学和免疫学，临床研究方法和临床 神经学我的长期目标是建立自己作为一个成功的独立的物理学家，科学家， 神经炎症和转化神经科学。为了实现这一目标，并促进我的过渡， 独立，我寻求5年的指导培训，通过国家卫生研究院K 08职业发展奖，以填补空白， 我的研究培训，建立未来研究合作者的网络，建立我的出版记录， 赠款写作技巧，并追求领导和教师发展的培训。 环境 埃默里大学的培训和指导环境非常适合我的职业发展。我的导师 埃默里大学的委员会由以下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 (Dr. Nicholas Seyfried），每个人都有NIH和非联邦资金的模范记录，领导了成功和 生产性研究小组和培养博士后和医生-科学家受训人员。我的导师和他们的 研究小组将为我提供以下方面的实践培训：（1）神经退行性疾病的动物模型， 促进翻译研究，（2）小胶质细胞和巨噬细胞的功能测定，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。我将接受研究 通过每周和每月的互动和直接监督我的研究进展， 在期刊俱乐部、研讨会以及地方和全国会议上发表演讲。我也会收到 神经胶质生物学，免疫学，神经科学研究的先进方法，生物信息学， R编程，系统生物学（加权相关网络分析）和负责任的行为 研究（>12个学分和满足NIH要求的面对面培训）。一队 具有系统生物学、肽合成、钾通道等专业知识的校内和校外贡献者 生物学和生物统计学也将指导拟议的研究。埃默里大学是一所大型学术机构 神经科学和神经病学获得NIH最高的研究资金之一（美国第9）。的 埃默里神经退行性疾病中心（CND）是一个合作和跨学科的研究 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 神经行为学方法 研究 阿尔茨海默病（AD）是痴呆症最常见的原因， 国际吧AD和其他疾病中单核吞噬细胞（MP）介导的免疫应答 越来越多的人认识到神经变性疾病通过促神经变性来影响神经变性， 炎症（疾病促进）和抗炎（保护）机制。选择性抑制剂， 减轻和/或促进抗炎作用的炎性功能可能导致新的 AD以及其他神经退行性疾病的疾病改善疗法。钾通道 是免疫功能的关键调节因子，我们的初步数据表明， 促炎MP功能受Kv1.3钾通道调节，而抗炎MP功能受Kv1.3钾通道调节。 功能由称为Kir2.1的不同K通道调节。在本提案中，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 体外活性氧产生、细胞因子/趋化因子产生;并将研究降低- 流信号传导和MP中Kv1.3和Kir2.1通道阻断的转录效应（Aim 1）。接下来我们就 确定这两种钾通道在外周血单核细胞源性 巨噬细胞和小胶质细胞从小鼠AD脑分离，并将测试这些通道是否调节 外周来源的MP在AD病理学小鼠模型中进入脑的能力（目的2）。最后我们 将使用新的高选择性和高选择性的药物对Kv1.3和Kir2.1通道的慢性阻断进行初步研究， 有效的阻滞剂作为缓解5xFAD中神经变性和认知缺陷的治疗策略 AD小鼠模型（目的3）。这项工作的结果将提供新的见解小胶质细胞和巨噬细胞 生物学，神经退行性疾病的免疫调节，并可能确定新的治疗策略 可以改变AD的疾病进展从这些研究目标中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（R 01）赠款和未来 跨神经退行性疾病和神经炎症疾病谱的合作研究。

项目成果

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

C反应蛋白作为住院的Covid-19患者的预后指标。

• 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