HIV, Gut Mucosal Turnover and Inflammation, and the Risk of Colorectal Neoplasia

HIV、肠道粘膜更新和炎症以及结直肠肿瘤的风险

• 批准号: 8538891
• 负责人: Ma Somsouk
• 金额: $ 17.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538891
• 关键词: AIDS related cancer; Adenomatous Polyps; Adherence; Affect; Archives; Atherosclerosis; Award; Biological; Biopsy; Cancer Biology; Carcinoma; Cell Survival; Clinic; Clinical Research; Clinical Trials; Cohort Studies; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Comorbidity; Data; Development; Disease; Environment; Epidemiology; Epithelial; Epithelial Cells; Epithelium; Funding; General Population; Goals; Guidelines; HIV; HIV Infections; HIV therapy; Human; Immune; Impaired cognition; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; K-Series Research Career Programs; Lamina Propria; Life Expectancy; Macaca; Malignant Neoplasms; Measures; Mediating; Medical; Mentors; Mentorship; Mesalamine; Methodology; Modeling; Mucositis; Mucous Membrane; Neoplasms; Parents; Pathogenesis; Pathway interactions; Positioning Attribute; Prevalence; Research; Research Infrastructure; Resources; Risk; SIV; Secondary to; Sigmoidoscopy; Specimen; Statistical Methods; Stromal Cells; T-Cell Activation; Tissues; Training; Translational Research; United States National Institutes of Health; Viral; adenoma; antiretroviral therapy; base; cancer prevention; career; clinically significant; cohort; colorectal cancer screening; cytokine; experience; high risk; immune activation; improved; insight; interdisciplinary approach; macrophage; meetings; microbial; nonhuman primate; novel; placebo controlled study; population based; prospective; repository; screening; senescence; skills; therapy design

ABSTRACT Population-based and endoscopic studies have suggested that the incidence of colorectal cancer (CRC) and its precursor, adenomatous polyps, is elevated in HIV-infected individuals compared with the general population. However, a specific mechanism explaining this high risk of colonic neoplasm has not been established. Gut epithelial turnover and mucosal inflammation are prominent in non-human primate models of HIV infection and is an important determinant of progressive HIV disease. Mucosal turnover and inflammation are further associated with the presence and development of adenoma in studies of uninfected individuals. The broad goal of this proposal is to characterize mucosal turnover and inflammation during HIV infection and their contribution to the risk of colorectal neoplasia. To this end, this application proposes (1) to determine the impact of untreated and treated HIV infection on mucosal turnover and inflammation compared to uninfected individuals, (2) to determine whether mucosal turnover and inflammation are associated with the presence of neoplasia in both HIV+ and HIV- individuals, and (3) to determine whether mesalamine decreases gut epithelial turnover and mucosal inflammation among HIV+ individuals in the context of an ongoing placebo-controlled trial. A major strength of this proposal is our ability to leverage a clinically well-characterized NIH-sponsored HIV-infected cohort (SCOPE) of over 1,360 subjects where 186 subjects have already undergone sigmoidoscopy and biopsies. Mucosal turnover and inflammation will be examined using archived tissue from SCOPE subjects (HIV treated, untreated, elite controllers, and uninfected) (aim 1). Recruitment from SCOPE will form the basis of a prospective cohort study correlating mucosal turnover and inflammation to colorectal neoplasia (aim 2). Aim 3 will measure the impact of mesalamine on mucosal turnover and inflammation as a substudy of a parent trial to reduce systemic inflammation in HIV-infected individuals. The resources from the K-award will allow me to rigorously examine mucosal changes secondary to HIV, develop a large cohort, build a tissue repository, and rapidly examine new hypotheses as they emerge. Indeed, this award will enable me to acquire didactic training, receive long-term mentorship, and hands-on research experience to become proficient in (1) conducting longitudinal clinical research, (2) clinic-based translational methodologies, and (3) advanced statistical methods promoting my transition to an independent research career. RELEVANCE: The current proposal will help confirm the HIV-attributable risk of colon cancer while providing important insights into the mechanisms mediating this risk. Our hypothesis derived from nonhuman primate studies is that HIV accelerates colonic epithelial cell turnover, which may drive the development of adenomas and carcinomas, is a logical and testable hypothesis and may have profound implications for the management of HIV disease, for informing appropriate screening guidelines, and for identifying targets for interventions in this setting. Moreover, disruption of the epithelial barrier also has important implications to HIV-associated comorbidities (e.g. systemic inflammation, cognitive decline, atherosclerosis, and immune senescence) to the extent that persistent microbial translocation increases the risk of these conditions via inflammatory pathways.

抽象的 基于人群的和内窥镜研究表明结直肠癌的发生率 癌症（CRC）及其前体腺瘤息肉在HIV感染的个体中升高 与一般人群相比。但是，一种解释这种高风险的特定机制 尚未建立结肠肿瘤。肠上皮周转和粘膜炎症 在艾滋病毒感染的非人类灵长类动物模型中是突出的，是 进行性艾滋病毒疾病。粘膜更新和炎症与 在未感染个体的研究中，腺瘤的存在和发展。广泛的目标 该建议是表征粘膜周转和艾滋病毒感染期间炎症及其炎症 对结直肠肿瘤风险的贡献。为此，本申请建议（1） 确定未经治疗和治疗的HIV感染对粘膜周转的影响 与未感染的个体相比，炎症，（2）确定粘膜的周转是否 炎症与HIV+和HIV-的肿瘤存在有关 个体，（3）确定美甲胺是否会降低肠道上皮周转率和 在持续的安慰剂对照的背景下，艾滋病毒+个体之间的粘膜炎症 审判。该提案的主要优势是我们能够利用临床表征良好的能力 超过1,360名受试者的NIH赞助的HIV感染队列（范围），其中186名受试者具有 已经进行了乙状结肠镜检查和活检。粘膜更新和炎症将是 使用范围受试者的存档组织检查（HIV处理，未经处理的精英控制器， 和未感染）（目标1）。范围招募将构成前瞻性队列的基础 研究将粘膜周转和炎症与结直肠瘤相关联（AIM 2）。目标3意志 测量美石胺对粘膜周转和炎症的影响 父母试验减少艾滋病毒感染者的全身性炎症。来自 a-award将使我能够严格检查继发于艾滋病毒的粘膜变化，发展 大型队列，建立组织存储库，并在出现时迅速检查新的假设。 确实，该奖项将使我能够接受教学培训，接受长期指导，并 动手研究经验，可以精通（1）进行纵向临床 研究，（2）基于诊所的翻译方法和（3）先进的统计方法 促进我向独立研究职业的过渡。相关性：当前提案 将有助于确认结肠癌的HIV征收风险，同时提供重要的见解 介导这种风险的机制。我们从非人类灵长类研究中得出的假设是 艾滋病毒加速了结肠上皮细胞更新，这可能会推动 腺瘤和癌是一个逻辑且可检验的假设，可能具有深刻的 对艾滋病毒疾病管理的影响，以告知适当的筛查指南， 并用于确定在这种情况下干预措施的目标。而且，上皮的破坏 障碍也对与HIV相关的合并症具有重要意义（例如，系统性 炎症，认知能力下降，动脉粥样硬化和免疫衰老） 持续的微生物易位通过炎症增加了这些疾病的风险 途径。