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: 8337392
• 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/8337392
• 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; Screening procedure; 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; 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 基于人群和内窥镜研究表明结直肠癌的发病率 HIV 感染者中癌症 (CRC) 及其前体腺瘤性息肉的发病率升高 与一般人群相比。然而，有一个具体的机制可以解释这种高风险 结肠肿瘤的发生尚未确定。肠上皮更新和粘膜炎症 在 HIV 感染的非人类灵长类动物模型中很突出，并且是 HIV 感染的重要决定因素 进行性艾滋病毒疾病。粘膜更新和炎症进一步与 在未感染个体的研究中发现腺瘤的存在和发展。广泛的目标是 该提案旨在描述 HIV 感染期间的粘膜更新和炎症及其影响 结直肠肿瘤风险的贡献。为此，本申请提出（1） 确定未经治疗和治疗的 HIV 感染对粘膜更新的影响，以及 与未感染个体相比，炎症，（2）确定粘膜更新是否 炎症与 HIV+ 和 HIV- 中肿瘤的存在有关 个体，以及（3）确定美沙拉嗪是否会降低肠道上皮更新和 在持续安慰剂对照的背景下，HIV + 个体的粘膜炎症 审判。该提案的一个主要优势是我们能够利用临床上充分表征的 NIH 赞助的 HIV 感染队列 (SCOPE)，包含超过 1,360 名受试者，其中 186 名受试者患有 已经接受了乙状结肠镜检查和活检。粘膜更新和炎症将 使用 SCOPE 受试者（HIV 治疗过的、未治疗过的、精英控制者、 且未受感染）（目标 1）。 SCOPE 的招募将构成未来队列的基础 将粘膜更新和炎症与结直肠肿瘤相关的研究（目标 2）。目标3将 测量美沙拉嗪对粘膜更新和炎症的影响作为一项子研究 减少艾滋病毒感染者全身炎症的家长试验。资源来自于 K 奖将使我能够严格检查继发于 HIV 的粘膜变化，开发一种 大型队列，建立组织存储库，并在新假设出现时快速检验它们。 事实上，这个奖项将使我能够获得教学培训，接受长期指导，并 熟练的实践研究经验（1）进行纵向临床 研究，(2) 基于临床的转化方法，以及 (3) 先进的统计方法 促进我向独立研究生涯的过渡。相关性：当前提案 将有助于确认艾滋病毒引起的结肠癌风险，同时提供重要的见解 调解这种风险的机制。我们从非人类灵长类动物研究中得出的假设是 HIV 加速结肠上皮细胞更新，这可能会推动结肠上皮细胞的发展 腺瘤和癌，是一个合乎逻辑且可检验的假设，可能具有深远的意义 对艾滋病毒疾病管理的影响，为适当的筛查指南提供信息， 并确定在此情况下的干预目标。此外，上皮细胞的破坏 屏障对 HIV 相关合并症也有重要影响（例如系统性 炎症、认知能力下降、动脉粥样硬化和免疫衰老） 持续的微生物易位会通过炎症增加这些疾病的风险 途径。