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.

摘要 基于人群的研究和内窥镜研究表明，结直肠癌的发病率 癌症（CRC）及其前体腺瘤性息肉在HIV感染者中的发病率升高 与一般人群相比。然而，解释这种高风险的具体机制 结肠肿瘤的发病率尚未确定。肠上皮更新和粘膜炎症 在HIV感染的非人灵长类动物模型中是突出的，并且是HIV感染的重要决定因素。 进行性艾滋病。粘液循环和炎症进一步与 在未感染个体的研究中发现腺瘤的存在和发展。的广泛目标 这项建议是为了表征HIV感染期间的粘膜更新和炎症， 增加结直肠肿瘤的风险。为此，本申请提出（1） 确定未经治疗和经治疗的HIV感染对粘膜更新的影响， 炎症相比，未感染的个人，（2）以确定是否粘膜营业额 和炎症都与HIV+和HIV-中的瘤形成有关 个体，和（3）确定美沙拉嗪是否降低肠上皮细胞的周转， 在正在进行的安慰剂对照的背景下， 审判该提案的一个主要优势是我们能够利用临床上特征良好的 NIH申办的HIV感染队列（SCOPE），超过1，360例受试者，其中186例受试者 已经做了乙状结肠镜检查和活检粘液周转和炎症将是 使用来自SCOPE受试者（HIV治疗的，未治疗的，精英控制者， 未感染）（目标1）。从SCOPE招募的人员将构成前瞻性队列的基础 将粘膜更新和炎症与结直肠肿瘤相关的研究（目的2）。目标3将 测量美沙拉嗪对粘膜更新和炎症的影响，作为 减少HIV感染者全身炎症的母体试验。提供的资源 K奖将使我能够严格检查继发于HIV的粘膜变化， 建立一个组织库，并在新假设出现时迅速对其进行检验。 事实上，这个奖项将使我能够获得教学培训，接受长期的指导， 实践研究经验，成为精通（1）进行纵向临床 研究，（2）基于临床的翻译方法，（3）先进的统计方法 促进我向独立研究方向的转变相关性：当前提案 将有助于确认结肠癌的HIV归因风险，同时提供重要的见解， 调节这种风险的机制。我们从非人类灵长类动物研究中得出的假设是， HIV加速了结肠上皮细胞的更新，这可能会推动结肠癌的发展。 腺瘤和癌，是一个合乎逻辑的和可检验的假设，并可能有深刻的 对艾滋病毒疾病管理的影响，为适当的筛查指南提供信息， 并确定在这种情况下的干预目标。此外，上皮细胞的破坏 屏障也对HIV相关的合并症（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。