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.项目摘要/摘要 心血管疾病在感染艾滋病毒的患者中非常普遍，然而， 人类免疫缺陷病毒感染患者动脉粥样硬化性疾病的发展尚不清楚。慢性艾滋病毒感染是 与胃肠粘膜上皮完整性丧失和肠道内CD4+T细胞丧失有关 固有层，导致胃肠道微生物移位增加。钥匙 这项拨款申请的假设是微生物易位导致先天免疫的激活。 可引起血管系统炎症损伤，导致心血管疾病的系统。这 应用建议研究肠粘膜屏障在先天性免疫激活和 对HIV感染者动脉粥样硬化性疾病的下游影响。 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(TO)通过动脉炎症来衡量心血管风险 评估动脉巨噬细胞活性)和冠状动脉CT血管造影术(评估 冠状动脉粥样硬化斑块的数量和质量)。单核细胞的转录分析是 提出在HIV感染患者中确定动脉粥样硬化形成的新生物途径。 为了进一步验证中心假设，在目标2中提出了一项旨在改善肠道上皮细胞的干预性研究 完整性和减少微生物移位，以测试这种干预对心血管的影响 炎症和单核细胞功能。胰升糖素样肽2类似物替杜鲁肽对急性胰腺炎的干预作用 已知的对肠道上皮的营养和抗炎作用，将在随机、 HIV感染者的双盲安慰剂对照概念验证试验。需要检验的假设 肠道上皮完整性的改善将降低肠道对微生物产品的通透性，从而 减少对单核细胞和巨噬细胞激活的刺激，从而降低巨噬细胞的活性 通过FDG-PET测量动脉壁中的脂肪含量，并降低总体心血管风险。