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

描述(申请人提供)：本申请的总体目标是研究胰岛素样生长因子2受体(IGF2R)在HIV相关神经认知障碍中的作用。拟议的K01指导研究将对我作为一名新的独立调查员的职业发展产生至关重要的影响，并将使我能够实现我的长期目标，即提高对与艾滋病毒/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重要作用，但由于IGF2R KO小鼠的围生期致死性，其在整个生物体中的出生后作用在很大程度上是未知的。我们已经获得了令人信服的数据，表明在HIV脑炎中，IGF2R在激活的小胶质细胞中强烈上调，并且IGF2R功能促进HIV的表达和小胶质细胞中趋化因子的产生。这些发现表明，IGF2R生物学先前未知的方面表明，IGF2R在巨噬细胞中的表达受到高度调控。由于IGF2R具有降解IGF多肽(IGF1和IGF2)的功能，在病毒感染过程中血清IGF水平降低，我们认为在病毒感染和炎症过程中，IGF2R在脑巨噬细胞中的过度表达导致IGF2和IGF1降解增加，从而剥夺了神经元必要的营养因子。我们进一步认为，IGF2R促进了小胶质细胞的前病毒和促炎活性，延续了艾滋病毒传播、炎症和神经元损伤的恶性循环。具体目标是：(1A)：确定患有/不患有脑炎的HIV携带者和HIV+者体内人中枢神经系统IGF2R表达的调节。(1E3)测定炎症刺激和感染刺激对体外培养的人小胶质细胞中IGF2R表达的调节；(2A)确定IGF2R在HIV感染小胶质细胞中的作用；(2B)确定IGF2R在小胶质细胞炎症基因表达中的作用；(3A)建立并鉴定巨噬细胞特异性的IGF2R KO小鼠；(3B)利用IGF2R KO小鼠，确定IGF2R在体内和体外HIV感染中的作用。在完成拟议的研究后，我将获得三个重要领域的培训：神经病理学、病毒学和动物研究，这些都是神经艾滋病研究的关键领域。通过计划的实验，结合现有的导师、教育计划和爱因斯坦的CFAR计划，循序渐进地进行，将确保成功地进行独立培训，以及实现本申请中概述的科学目标。公共卫生相关性IGF2R是一种以前没有在脑巨噬细胞中研究过的蛋白质。基于令人信服的数据证明其在HIV感染过程中的新表达，研究人员提出了一个新的假设，即脑巨噬细胞在维持大脑中胰岛素样生长因子肽平衡方面发挥核心作用，并且在HIV感染过程中这一过程的失调可能导致神经退化。

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.