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

基本信息

批准号：
8846667
负责人：
Janet Lo
金额：
$ 81.01万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8846667
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 Health Heart 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 cardiovascular visualization 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 teduglutide transcriptome sequencing transcriptomics treatment strategy vascular inflammation

项目摘要

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.

描述（由申请人提供）：心血管疾病在 HIV 感染者中非常普遍，然而 HIV 感染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丧失和肠固有层 CD4+ T 细胞丧失有关，导致胃肠道微生物易位增加。该拨款申请的关键假设是微生物易位会导致先天免疫系统激活，从而诱发脉管系统炎症损伤，从而导致心血管疾病。目标 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心血管风险的关系，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（评估冠状动脉粥样硬化斑块）测量动脉炎症定量和定性）。建议对单核细胞进行转录组分析，以确定 HIV 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 提出了一项干预研究，以改善肠道上皮完整性并减少微生物易位，以测试这种干预对心血管炎症和单核细胞功能的影响。替度鲁肽（一种胰高血糖素样肽 2 类似物，已知对肠上皮具有营养和抗炎作用）的干预作用将在 HIV 感染者中进行随机、双盲安慰剂对照概念验证试验中进行研究。待测试的假设是，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，从而减少对单核细胞和巨噬细胞活化的刺激，从而降低 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。