Insulin-like growth factor 2 receptor in CNS viral infection and inflammation

中枢神经系统病毒感染和炎症中的胰岛素样生长因子2受体

• 批准号: 8261984
• 负责人: Hyeon-Sook Suh
• 金额: $ 15.3万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-06 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261984
• 关键词: AIDS neuropathy; AIDS/HIV problem; Achievement; Amino Acids; Animals; Area; Binding; Biology; Brain; Cells; Central Nervous System Viral Diseases; Cytoplasmic Tail; Data; Development; Disease; Encephalitis; Ensure; Enzymes; Equilibrium; Fetal Development; Gene Expression; Goals; Golgi Apparatus; HIV; HIV Infections; HIV encephalitis; Health; Human; IGF1 gene; ITGAM gene; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Insulin Receptor; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Interferon Type II; Lead; Ligands; Literature; Lysosomes; Malignant Neoplasms; Mentors; Mentorship; Microglia; Mus; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neuroglia; Neurons; Pathogenesis; Peptides; Perinatal; Play; Process; Production; Proteins; Receptor Signaling; Regulation; Research; Research Personnel; Role; Serum; Signal Transduction; Small Interfering RNA; Somatomedins; Sorting - Cell Movement; Stimulus; Technology; Toll-like receptors; Training; Tumor Suppressor Genes; Virus Diseases; Whole Organism; base; career development; chemokine; cytokine; extracellular; human IGF2R protein; improved; in vivo; macrophage; mannose 6 phosphate; nervous system disorder; neuropathology; novel; postnatal; prevent; programs; receptor; receptor expression; receptor function; research study; trafficking; virology

DESCRIPTION (provided by applicant): The overall goal of this application is to investigate the role of insulin-like growth factor 2 receptor (IGF2R) in HIV-associated neurocognitive disorders. The proposed K01 mentored research will critically influence my career development as a new independent investigator and will enable me to fulfill my long-term objective of improving the understanding and treatment of nervous system disorders associated with HIV/AIDS. IGF2R has a crucial function in fetal development and in lysosomal enzyme trafficking but due to the perinatal lethality of the global IGF2R KO mouse, its postnatal role in the whole organism is largely unknown. We have obtained compelling data that indicate that IGF2R is robustly upregulated in activated microglia in HIV encephalitis and that IGF2R functions to promote HIV expression and chemokine production in microglia. These findings suggest previous unknown aspects of IGF2R biology that IGF2R expression is highly regulated in macrophages. Since IGF2R functions to degrade IGF peptides (IGF1 and IGF2) and serum IGF levels are reduced during viral infection, we propose that over-expression of IGF2R in brain macrophages during viral infection and inflammation leads to increased degradation of IGF2 and IGF1, depriving neurons of the necessary trophic factors. We further propose that IGF2R promotes the proviral and proinflammatory activity of microglia, perpetuating the vicious cycle of HIV spread, inflammation and neuronal damage. Specific Aims are (1A): to determine the regulation of IGF2R expression in human CNS in vivo of HIV- and HIV+ individuals with/without encephalitis. (1E3) Determine the regulation of IGF2R expression in human microglia in vitro by inflammatory and infectious stimuli; (2A) to determine the role of IGF2R in HIV infection of microglia in vitro; (2B) to determine the role of IGF2R in microglial inflammatory gene expression; (3A) to generate and characterize macrophage-specific IGF2R KO mice; (3B) to determine the function of IGF2R in HIV infection in vivo and in vitro using the IGF2R KO mice. Upon completion of the proposed studies, I will have attained training in three important areas: neuropathology, virology and in animal studies, all crucial areas of neuroAIDS research. A step-wise progression through the planned experiments combined with the available mentorship, educational programs and the CFAR program at Einstein will ensure successful training towards independence, as well as achievement of the scientific goals outlined in this application. PUBLIC HEALTH RELEVANCE The IGF2R is a protein not previously investigated in brain macrophages. Based on the compelling data demonstrating its new expression during HIV infection, the investigators propose a novel hypothesis that brain macrophages play a central role in maintaining the insulin-like growth factor peptide balance in the brain and that dysregulation of this process during HIV infection can lead to neurodegeneration.

描述（由申请人提供）：本应用的总体目标是研究胰岛素样生长因子2受体（IGF2R）在与HIV相关的神经认知障碍中的作用。拟议的K01指导研究将严重影响我作为新的独立研究者的职业发展，并使我能够实现我的长期目标，以提高对与艾滋病毒/艾滋病相关的神经系统疾病的理解和治疗。 IGF2R在胎儿发育和溶酶体酶运输中具有至关重要的功能，但由于全球IGF2R KO小鼠的围产期致死性，其在整个生物体中的作用在很大程度上是未知的。我们获得了引人注目的数据，表明在HIV脑炎中活化的小胶质细胞中IGF2R牢固上调，并且IGF2R功能可促进小胶质细胞中HIV表达和趋化因子产生。这些发现表明，IGF2R生物学的先前未知方面表明，IGF2R表达在巨噬细胞中受到了高度调节。由于IGF2R在病毒感染过程中降解IGF肽（IGF1和IGF2）和血清IGF水平的功能降低，因此我们建议在病毒巨噬细胞中IGF2R过表达在病毒感染和炎症期间的脑巨噬细胞中的过表达，而IGF2和IGF2的去降解增加了IGF2和IGF1的去降解。我们进一步提出，IGF2R促进小胶质细胞的前炎和促炎活性，从而使HIV扩散，炎症和神经元损害的恶性循环永存。具体目的是（1a）：确定HIV-和HIV+患有/没有脑炎的HIV和HIV+个体的人CNS中IGF2R表达的调节。 （1E3）通过炎症和感染性刺激确定体外人类小胶质细胞中IGF2R表达的调节； （2a）确定IGF2R在体外小胶质细胞感染中的作用； （2b）确定IGF2R在小胶质细胞炎症基因表达中的作用； （3a）生成和表征巨噬细胞特异性的IGF2R KO小鼠； （3B）使用IGF2R KO小鼠确定IGF2R在体内和体外的HIV感染中的功能。拟议的研究完成后，我将在三个重要领域接受培训：神经病理学，病毒学和动物研究，这是神经辅助研究的所有关键领域。通过计划的实验进行的逐步发展，结合了爱因斯坦的可用指导，教育计划和CFAR计划，将确保成功培训独立性，并实现本应用程序中概述的科学目标。公共卫生相关性IGF2R是以前未在脑巨噬细胞中研究的蛋白质。基于引人注目的数据证明了其在HIV感染期间的新表达，研究者提出了一种新的假设，即脑巨噬细胞在维持大脑中胰岛素样生长因子肽平衡中起着核心作用，而HIV感染期间该过程的失调可能导致神经变性。