STAT3 and astrogliogenesis in HIV-1 associated dementia

描述（由申请人提供）：活跃的神经发生发生在整个生命过程中，依赖于神经干/祖细胞（npc）的增殖、迁移和适当分化。成人神经发生减少被认为是hiv -1相关痴呆（HAD）发病的一个潜在因素。在HAD中，hiv -1感染和免疫激活的脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）驱动中枢神经系统（CNS）炎症，并可能改变正常的神经发生。我们之前证明了hiv -1感染和激活的MP抑制神经发生，同时通过分泌炎性细胞因子如IL-1b和TNF-a，在体外和体内增强星形胶质细胞的发生。我们的初步研究表明，IL-1b和TNF-a，以及hiv -1感染和lps激活的MP诱导STAT3激活，这是星形胶质细胞形成的一个关键途径。此外，抑制STAT3激活、促进神经元分化和抑制星形胶质细胞分化的microRNA-9 （miR-9）和脑特异性microRNA-124 （miR-124）在细胞因子（IL-1b和TNF-a）治疗下降低。基于这些观察结果，我们假设hiv -1感染和免疫激活的MP通过STAT3途径通过分泌因子（包括细胞因子（IL-1b和TNF-a））促进NPC星形胶质细胞形成，miR-9和miR-124通过调节STAT3激活来调节这一过程。在本研究中，我们将研究炎症细胞因子（包括IL-1b和TNF-a）和hiv -1感染和免疫激活的MP刺激后NPCs中的STAT3通路，并研究其对星形胶质细胞形成的影响。我们还将研究mirna （miR-9和miR-124）在STAT3激活和细胞因子（IL-1b和TNF-a）和hiv -1感染和激活的MP介导的人鼻咽癌分化调节中的作用。我们将使用原代人鼻咽癌培养系统和严重联合免疫缺陷（SCID） HIV-1脑炎（HIVE）小鼠模型来验证这一假设。这项研究将产生重要的数据，破译在中枢神经系统进行性HIV-1感染期间脑炎症在神经发生中的作用。此外，这项工作还将确定神经干细胞治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Active neurogenesis occurs throughout life and relies upon the proliferation, migration and proper differentiation of neural stem/progenitor cells (NPCs). Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and activated MP inhibit neurogenesis, while enhancing astrogliogenesis in vitro and in vivo, through secretion of inflammatory cytokines such as IL-1b and TNF-a. Our preliminary study showed both IL-1b and TNF-a, as well as HIV-1-infected and LPS-activated MP induced STAT3 activation, a critical pathway of astrogliogenesis. Furthmore, microRNA-9 (miR-9) and brain-specific microRNA-124 (miR-124), factors shown to inhibit STAT3 activation, promote neuronal differentiation and inhibit astrocyte differentiation, are decreased in response to cytokine (IL-1b and TNF-a) treatment. Based on these observations, we hypothesize that HIV-1-infected and immune-activated MP promote NPC astrogliogenesis through secreted factors including cytokines (IL-1b and TNF-a) via the STAT3 pathway, and that miR-9 and miR-124 regulate this process through modulation of STAT3 activation. In this proposal, we will study the STAT3 pathway in NPCs following stimulation with inflammatory cytokines (including IL-1b and TNF-a) and HIV-1-infected and immune-activated MP and examine the effect on astrogliogenesis. We will also investigate the role of miRNAs (miR-9 and miR-124) in STAT3 activation and the modulation of human NPC differentiation mediated by cytokines (IL-1b and TNF-a) and HIV-1-infected and activated MP. We will test this hypothesis using a primary human NPC culture system and a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model. This research will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS. In addition, the work will also identify potential targets for therapeutic intervention for neural stem cell therapy. PUBLIC HEALTH RELEVANCE: Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia, in which HIV-1-infected and immune-activated macrophages drive central nervous system (CNS) inflammation. The study of the factors produced by these inflammatory cells and the signaling pathways involved in neural stem/progenitor cell differentiation will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS, and identify potential targets for therapeutic intervention for neural stem cell therapy.