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.
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.
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