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（由申请人提供）：基于人群的和内窥镜研究表明，与一般人群相比，在HIV感染的个体中，结直肠癌（CRC）及其前体腺瘤息肉的发生率升高。但是，尚未建立一种解释这种高风险的特定机制。肠道上皮周转和粘膜炎症在HIV感染的非人类灵长类动物模型中是突出的，并且是进行性HIV疾病的重要决定因素。在未感染个体的研究中，粘膜更新和炎症与腺瘤的存在和发育进一步相关。该提案的广泛目标是表征HIV感染期间粘膜周转和炎症及其对结直肠肿瘤风险的贡献。 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正在进行的安慰剂对照试验的背景。该提议的主要优势是我们的能力 利用临床表征良好的NIH赞助的HIV感染队列（范围），该队列（范围）超过1,360名受试者，其中186名受试者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范围受试者的存档组织（HIV处理，未经处理，精英控制器和未感染）检查（AIM 1）。从范围招募将构成一项前瞻性队列研究的基础，该研究将粘膜离职率和炎症与大肠肿瘤相关联（AIM 2）。 AIM 3将衡量美赛胺对粘膜更新和炎症的影响，作为父母试验的一种方法，以减少感染HIV感染的个体的全身性炎症。 K-award的资源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，并迅速检查出新的假设。的确，该奖项将使我能够接受教学培训，接受长期指导和动手研究经验，以精通（1）进行纵向临床研究，（2）基于诊所的转化方法，以及（3）高级统计方法，促进我的过渡到独立研究。相关性：当前的提案将有助于确认结肠癌的HIV侵占风险，同时为介导这种风险的机制提供重要的见解。我们源自非人类灵长类动物研究得出的假设是，HIV加速了结肠上皮细胞更新，这可能会推动腺瘤和癌的发展，这是一个合乎逻辑且可检验的假设，并且可能对HIV疾病的管理具有深远的影响，以确定适当的筛查指南，并在此设置中识别干预措施。此外，上皮屏障的破坏也对与HIV相关的合并症（例如，全身性炎症，认知能力下降，动脉粥样硬化和免疫衰老）具有重要意义，以至于持续的微生物易位会通过炎症途径增加这些情况的风险。