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: 8241527
• 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/8241527
• 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

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：基于人群和内窥镜的研究表明，与普通人群相比，HIV感染者的结直肠癌(CRC)及其前驱疾病--腺瘤性息肉的发病率更高。然而，解释这种结肠癌高风险的具体机制尚未建立。肠道上皮周转和粘膜炎症在非人类灵长类动物的HIV感染模型中是突出的，是进行性HIV疾病的重要决定因素。在对未感染个体的研究中，粘膜周转和炎症与腺瘤的存在和发展进一步相关。这项建议的广泛目标是描述HIV感染期间的粘膜周转和炎症及其对结直肠肿瘤风险的贡献。为此，本申请建议(1)确定未经治疗和经治疗的HIV感染对黏膜周转和炎症的影响，(2)确定黏膜周转和炎症是否与HIV+和HIV-患者中肿瘤的存在有关，以及(3)在正在进行的安慰剂对照试验的背景下，确定美沙拉明是否降低了HIV+患者的肠道上皮周转和黏膜炎症。这项提议的一个主要优势是我们有能力 利用NIH赞助的1,360多名受试者的临床特征良好的HIV感染队列(范围)，其中186名受试者已经接受乙状结肠镜检查和活组织检查。黏膜周转和炎症将使用来自范围受试者(艾滋病毒治疗、未治疗、精英控制员和未感染)的存档组织进行检查(目标1)。来自Scope的招募将形成一项前瞻性队列研究的基础，该研究将粘膜周转和炎症与结直肠肿瘤联系起来(目标2)。目的3将测量美沙拉明对粘膜周转和炎症的影响，作为减少HIV感染者全身炎症的亲本试验的子研究。来自K奖的资源将使我能够严格检查继发于HIV的粘膜变化，开发一个大的队列，建立一个组织仓库，并在新的假设出现时迅速检查它们。事实上，这一奖项将使我能够获得教学培训、长期指导和实践研究经验，从而精通(1)进行纵向临床研究，(2)以临床为基础的翻译方法，(3)促进我向独立研究生涯过渡的先进统计方法。相关性：目前的提案将有助于确认结肠癌的艾滋病毒可归因性风险，同时为调节这一风险的机制提供重要的见解。我们从非人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，这可能会驱动腺瘤和癌症的发展，这是一个合乎逻辑和可验证的假设，可能对HIV疾病的管理、提供适当的筛查指南以及确定干预目标具有深远的影响。此外，上皮屏障的破坏也对HIV相关的共病(如全身性炎症、认知功能减退、动脉粥样硬化和免疫衰老)具有重要意义，因为持续的微生物易位通过炎症途径增加了这些疾病的风险。