Targeting GI Epithelial Integrity to Improve Arterial Inflammation in HIV

以胃肠道上皮完整性为目标来改善艾滋病毒的动脉炎症

• 批准号: 8731433
• 负责人: Janet Lo
• 金额: $ 82.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731433
• 关键词: Address; Affect; Angiography; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Biological; Blood Circulation; Blood Vessels; CD4 Positive T Lymphocytes; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Chronic; Communicable Diseases; Coronary; Coronary Arteriosclerosis; Data; Development; Disease; Double-Blind Method; Endocrinology; Epithelial; Event; Functional Imaging; Gastroenterology; Gastrointestinal tract structure; Gene Expression Profile; General Hospitals; Genetic Crossing Over; Genomics; Goals; HIV; HIV Infections; Heart; Image; Immune system; Immunology; Individual; Inflammation; Inflammatory; Institutes; Intervention; Intervention Studies; Intestines; Laboratories; Lamina Propria; Lead; Life; Link; Macrophage Activation; Massachusetts; Measures; Mucosal Immunity; Pathologic; Pathway interactions; Patients; Permeability; Placebo Control; Positron-Emission Tomography; Process; Radiology Specialty; Randomized; Research Personnel; Role; Stimulus; Testing; Tight Junctions; Time; Tissues; X-Ray Computed Tomography; analog; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; disorder risk; double-blind placebo controlled trial; gastrointestinal; glucagon-like peptide; immune activation; improved; intestinal epithelium; macrophage; microbial; monocyte; mortality; multidisciplinary; novel; patient population; prevent; public health relevance; teduglutide; transcriptome sequencing; transcriptomics; treatment strategy; vascular inflammation

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.

7. 项目概要/摘要 心血管疾病在 HIV 感染者中非常普遍，然而，心血管疾病的不同机制 HIV 感染者的动脉粥样硬化疾病发展尚不清楚。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 CD4+ T 细胞丧失相关 固有层，导致胃肠道微生物移位增加。关键 该拨款申请的假设是微生物易位导致先天免疫激活 系统，可引起脉管系统炎症损伤，导致心血管疾病。这 该申请旨在研究肠粘膜屏障对先天免疫激活和 对艾滋病毒感染者动脉粥样硬化疾病的下游影响。 目标 1 旨在研究肠上皮完整性和微生物易位至单核细胞的关系 和巨噬细胞活化以及通过 FDG-PET 通过动脉炎症测量的心血管风险（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（评估 冠状动脉粥样硬化斑块的定量和定性）。单核细胞的转录组分析是 提议确定艾滋病毒感染患者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，目标 2 中提出了一项改善肠道上皮细胞的干预研究 完整性并减少微生物移位，以测试这种干预措施对心血管的影响 炎症和单核细胞功能。替度鲁肽（一种胰高血糖素样肽 2 类似物）的干预 已知对肠上皮的营养和抗炎作用，将通过随机、 在艾滋病毒感染者中进行双盲安慰剂对照概念验证试验。待检验的假设 肠道上皮完整性的改善将降低肠道对微生物产物的通透性，因此 减少对单核细胞和巨噬细胞活化的刺激，从而降低巨噬细胞的活性 通过 FDG-PET 测量动脉壁，降低总体心血管风险。