Targeting GI Epithelial Integrity to Improve Arterial Inflammation in HIV

描述（由申请人提供）：心血管疾病在HIV感染患者中高度流行，然而HIV感染患者中动脉粥样硬化疾病发展的独特机制尚不清楚。慢性HIV感染与胃肠道粘膜上皮完整性的丧失和肠固有层中CD 4 + T细胞的丧失相关，导致胃肠道微生物易位增加。这项拨款申请的关键假设是微生物易位导致天然免疫系统激活，这可能诱导血管系统的炎症损伤，导致心血管疾病。目的1旨在研究肠上皮完整性和微生物易位与单核细胞和巨噬细胞活化以及通过FDG-PET（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（定量和定性评估冠状动脉粥样硬化斑块）通过动脉炎症测量的心血管风险的关系。单核细胞中的转录组学分析被提出来鉴定HIV感染患者中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，在目的2中提出了一项干预性研究，以改善肠道上皮完整性并减少微生物易位，以检验这种干预对心血管炎症和单核细胞功能的影响。将在HIV感染者中进行的一项随机、双盲、安慰剂对照的概念验证试验中研究替度鲁肽（一种已知对肠上皮具有营养和抗炎作用的胰高血糖素样肽2类似物）的干预作用。待检验的假设是，肠上皮完整性的改善将降低肠道对微生物产物的渗透性，从而降低对单核细胞和巨噬细胞活化的刺激，并因此降低通过FDG-PET测量的动脉壁中的巨噬细胞活性并降低总体心血管风险。

DESCRIPTION (provided by applicant): 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 innat immune system which can induce inflammatory damage in the vasculature, leading to cardiovascular disease. 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 te stimulus for monocyte and macrophage activation, and therefore decrease macrophage activity in the arterial wall measured by FDG-PET and reduce overall cardiovascular risk.