Pre-Exposure Prophylaxis (PrEP) inhibits oligodendrocyte differentiation in vivo

项目概要： 每年，13至24岁的人不成比例地构成被诊断患有 人类免疫缺陷病毒（HIV）在美国。接触前预防，a 每天一次的抗逆转录病毒疗法，是预防艾滋病毒传播的有效方法， 青少年在获得艾滋病毒的巨大风险，但是，这种方案的影响， 青春期大脑关键结构的发育是未知的。服用PrEP的青少年 特别容易受到髓鞘损伤，因为青少年的大脑正在经历高比率 髓鞘形成我们的实验室已经表明，原代少突胶质细胞前体细胞培养处理 治疗浓度的选择抗逆转录病毒药物显示出剂量依赖性 减少少突胶质细胞成熟。我们知识上的空白，是人类进化的机械基础。 抗逆转录病毒药物抑制HIV阴性青少年少突胶质细胞成熟 人口我的初步数据表明，恩曲他滨（FTC）和替诺福韦酯 富马酸盐（TDF），组成PrEP的药物，使少突胶质细胞溶酶体去酸化。此外，委员会认为， 我的初步数据还表明，PrEP降低了少突胶质细胞中SREBP 2的表达， 体外mTORC 1通过转录因子SREBP 1和2调节脂肪生成， 后者调节参与胆固醇合成的基因的表达，即限速步骤， 髓鞘形成已显示溶酶体去酸化导致mTORC 1增加 在破骨细胞中的信号传导，但在少突胶质细胞中仍有待研究。此外，本发明还 已知少突胶质细胞中mTORC 1的过度活化导致髓鞘形成不足， SREBP 2表达降低。综上所述，我推测少突胶质细胞的成熟 PrEP通过溶酶体脱酸抑制mTORC 1的活化， 和脂肪生成减少。我将在以下具体目标中阐述这一假设。目标1 我将证明少突胶质细胞的成熟是受损的PrEP通过溶酶体去- 体外酸化。在目标2中，我将证明PrEP抑制少突胶质细胞成熟 通过增加mTORC 1信号传导和随后的体外脂肪生成减少。在目标3中， 我将证明少突胶质细胞的成熟和髓鞘形成受到PrEP的损害， 溶酶体酸化在体内挽救髓鞘形成。总的来说，这些实验将研究 关于PrEP是否影响HIV中少突胶质细胞成熟的先前未回答的问题- 消极的个人。

PROJECT SUMMARY: Each year 13- to 24-year-olds disproportionately compose the number individuals diagnosed with human immunodeficiency virus (HIV) in the United States. Preexposure prophylaxis (PrEP), a once daily antiretroviral regime, is an effective method to prevent the transmission of HIV in adolescents at substantial risk for acquiring HIV, however, the effect of this regimen on the development of critical brain structures during adolescence is unknown. Adolescents taking PrEP are uniquely vulnerable to myelin impairments as the adolescent brain is undergoing high rates of myelination. Our lab has shown that primary oligodendrocyte precursor cell cultures treated with therapeutic concentrations of select antiretroviral drugs displayed dose-dependent decreases in oligodendrocyte maturation. A gap in our knowledge is the mechanistic basis of the inhibition of oligodendrocyte maturation by antiretrovirals in an HIV-negative, adolescent population. My preliminary data suggests that emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), the drugs composing PrEP, de-acidify oligodendrocyte lysosomes. Furthermore, my preliminary data also suggests that PrEP decreases SREBP2 expression in oligodendrocytes in vitro. mTORC1 regulates lipogenesis through the transcription factors SREBP 1 and 2, with the latter regulating the expression of genes involved in cholesterol synthesis, the rate-limiting step of myelination. Lysosome de-acidification has been shown to result in increased mTORC1 signaling in osteoclasts but remains to be investigated in oligodendrocytes. Additionally, overactivation of mTORC1 in oligodendrocytes is known to result in hypomyelination and decreased SREBP2 expression. Taken together, I hypothesize that oligodendrocyte maturation is inhibited by PrEP through lysosome deacidification resulting in increased mTORC1 activation and decreased lipogenesis. I will address this hypothesis in the following specific aims. In Aim 1 I will demonstrate oligodendrocyte maturation is impaired by PrEP through lysosome de- acidification in vitro. In Aim 2, I will demonstrate that PrEP inhibits oligodendrocyte maturation through increased mTORC1 signaling and subsequent decreased lipogenesis in vitro. In Aim 3, I will demonstrate that oligodendrocyte maturation and myelination are impaired by PrEP and lysosome acidification rescues myelination in vivo. Overall, these experiments will investigate the previously unanswered question of whether PrEP affects oligodendrocyte maturation in HIV- negative individuals.