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

点击翻译按钮获取中文摘要

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.