Targeting GI Epithelial Integrity to Improve Arterial Inflammation in HIV

7.项目总结/摘要 心血管疾病在艾滋病毒感染者中非常普遍，然而， HIV感染患者中动脉粥样硬化疾病的发展尚不清楚。慢性艾滋病毒感染是 与胃肠道粘膜上皮完整性丧失和肠道中CD 4 + T细胞丧失相关 固有层，导致增加的微生物易位通过胃肠道。关键 这项拨款申请的假设是微生物易位引起先天免疫的激活 系统，可诱导脉管系统中的炎性损伤，导致心血管疾病。这 该申请提出研究肠粘膜屏障对先天免疫激活的作用， HIV感染患者动脉粥样硬化疾病的下游效应。 目的1研究肠道上皮完整性与微生物向单核细胞移位的关系 和巨噬细胞活化以及通过FDG-PET测量的动脉炎症的心血管风险（以 评估动脉巨噬细胞活性）和冠状动脉心脏计算机断层扫描血管造影术（以评估 冠状动脉粥样硬化斑块定量和定性）。单核细胞中的转录组学分析是 提出在HIV感染患者中识别动脉粥样硬化形成的新生物学途径。 为了进一步检验中心假设，在目标2中提出了一项干预性研究，以改善肠道上皮细胞的生长。 完整性和减少微生物易位，以测试这种干预对心血管疾病的影响。 炎症和单核细胞功能。胰高血糖素样肽2类似物替度鲁肽的干预作用 已知的对肠上皮的营养和抗炎作用，将在随机， 在HIV感染者中进行的双盲安慰剂对照概念验证试验。待测试的假设 肠道上皮完整性的改善将降低肠道对微生物产物的渗透性，因此 减少单核细胞和巨噬细胞活化的刺激，从而降低巨噬细胞活性 通过FDG-PET测量的动脉壁中的浓度，并降低总体心血管风险。

7. PROJECT SUMMARY/ ABSTRACT Cardiovascular disease is highly prevalent among HIV-infected patients, however the distinct mechanisms of atherosclerotic disease development in HIV-infected patients are yet unknown. Chronic HIV infection is associated with loss of gastrointestinal mucosal epithelial integrity and loss of CD4+ T-cells in the intestinal lamina propria, leading to increased microbial translocation across the gastrointestinal tract. The key hypothesis of this grant application is that microbial translocation causes activation of the innate immune system which can induce inflammatory damage in the vasculature, leading to cardiovascular disease. This application proposes to investigate the role of the intestinal mucosal barrier to innate immune activation and downstream effects on atherosclerotic disease in HIV-infected patients. Aim 1 seeks to study the relationships of intestinal epithelial integrity and microbial translocation to monocyte and macrophage activation and to cardiovascular risk measured by arterial inflammation via FDG-PET (to assess arterial macrophage activity) and coronary cardiac computed tomography angiography (to assess coronary atherosclerotic plaque quantitatively and qualitatively). Transcriptomic analyses in monocytes are proposed to identify novel biological pathways of atherogenesis in HIV-infected patients. To further test the central hypothesis, an interventional study is proposed in Aim 2 to improve the gut epithelial integrity and reduce microbial translocation in order to test effects of such an intervention on cardiovascular inflammation and monocyte function. The intervention of teduglutide, a glucagon-like peptide 2 analog with known trophic and anti-inflammatory effects on the intestinal epithelium, will be investigated in a randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals. The hypothesis to be tested is that improvement of gut epithelial integrity will decrease intestinal permeability to microbial products, thus decreasing the stimulus for monocyte and macrophage activation, and therefore decrease macrophage activity in the arterial wall measured by FDG-PET and reduce overall cardiovascular risk.