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 候选人 我是一名经过委员会认证的神经科医生，致力于以健康为导向的基础和转化研究。 具有离子通道生物学和免疫学、临床研究方法和临床研究方面的专业知识 我的长期目标是使自己成为一名成功的独立医师科学家。 为了实现这一目标并促进我向神经炎症和转化神经科学的过渡。 独立，我通过 NIH K08 职业发展奖寻求 5 年的指导培训，以填补以下方面的空白 我的研究培训，建立未来研究合作者的网络，建立我的发表记录以及 资助写作技能并接受领导力和教师发展方面的培训。 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。 埃默里大学委员会由以下领域的专家和独立科学家组成： 神经退行性疾病（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），每个人都拥有 NIH 和非联邦资助的典范记录，领导了成功和 富有成效的研究小组和培训博士后和医师科学家实习生我的导师和他们。 研究小组将为我提供以下方面的实践培训：（1）神经退行性变动物模型作为工具 促进转化研究，(2) 小胶质细胞和巨噬细胞的功能测定、免疫信号传导、 我将接受免疫分析、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的研究。 通过每周和每月的互动进行指导并直接监督我的研究进展， 我还将收到在期刊俱乐部、研讨会上的演讲以及在地方和国家会议上的演讲。 神经胶质生物学、免疫学、神经科学研究先进方法、生物信息学的正式课程， R 编程、系统生物学（WeiGhted Correlation Network Analysis）以及负责任的行为 埃默里大学的研究（>12 个学分和满足 NIH 要求的现场培训） 具有系统生物学、肽合成、钾通道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了 NIH 最高的研究经费之一（美国排名第 9）。 埃默里神经退行性疾病中心 (CND) 是一个协作性跨学科研究中心 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 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) 缺乏疾病缓解疗法，阿尔茨海默氏病是痴呆症最常见的病因 AD 和其他疾病中单核吞噬细胞 (MP) 介导的免疫反应。 人们越来越认识到神经退行性疾病通过促 炎症（促进疾病）和抗炎（保护）机制。 抑制和/或促进抗炎作用的炎症功能可能会导致新型药物的开发 AD 以及其他神经退行性疾病的疾病缓解疗法。 大脑中 MP 表达的蛋白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 活性氧的产生、细胞因子/趋化因子的体外产生； MPs 中 Kv1.3 和 Kir2.1 通道阻断的流信号传导和转录效应（目标 1）。 确定这两种钾通道在外周血单核细胞来源中的表达模式 从小鼠 AD 大脑中分离出巨噬细胞和小胶质细胞，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大脑的能力（目标 2）。 将使用新颖的高选择性和 有效的阻滞剂作为减轻 5xFAD 神经退行性变和认知缺陷的治疗策略 AD 小鼠模型（目标 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、神经退行性疾病的免疫调节，并可能确定新的治疗策略 这些研究目标产生的数据也将推动 AD 疾病的进展。 候选人的职业发展，并将导致未来的独立调查员（R01）资助和未来 跨神经退行性疾病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