Molecular Epidemiology of Recurrent Aphthous Stomatitis: Role of Ghrelin

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DESCRIPTION (provided by applicant): Recurrent aphthous stomatitis (RAS) is one of the most common and poorly understood oral mucosal disorders. Affected individuals experience recurrent painful oral ulcerations ranging in size from a few mm to over 1/2 inch. RAS lesions may be a manifestation of a systemic disorder or they may occur in apparently healthy individuals. The cyclic nature of RAS lesions, their peak prevalence during the 2nd decade and familial clustering suggest that environmental, age-dependent and genetic factors are likely involved. Despite extensive research over the past five decades, the etiopathogenesis of RAS is still unknown. As a result, current treatments are mostly palliative and ineffective in preventing recurrences long-term. Ghrelin is a recently discovered peptide with multiple functions including regulation of growth, gastroprotection and inhibition of inflammatory cytokines. Our studies also indicate that factors affecting plasma ghrelin overlap with risk factors for RAS. Thus, we hypothesize that a ghrelin deficit is associated with RAS onset. The overall aim of this study is to determine whether ghrelin expression and circulating levels are altered in RAS. We will recruit participants from the population served by the University of Florida. We will collect data through questionnaires, examinations, blood and salivary measurements, and surgical biopsies. Specific Aim 1 (Circulating ghrelin): We will compare fasting total plasma ghrelin levels (1) in 60 cases (30 with and 30 without active ulcers) vs. 50 unrelated controls using an unmatched case-control design and (2) in 40 cases during their active vs. inactive phase using a non-randomized crossover design. Enzyme-linked immunosorbent assay (ELISA) data will be analyzed using analysis of covariance, logistic regression and paired t-tests in SAS v9.1. Additionally, we will perform secondary epidemiologic analyses comparing ghrelin-related signs and symptoms in these groups. Specific Aim 2 (Ghrelin protein expression): We will conduct a pilot study to compare ghrelin and ghrelin receptors (growth hormone secretagogue receptors GHS-R1a and GHS-R1b) protein expression (1) in ulcerated tissue from active cases vs. normal tissue from controls and (2) in ulcerated vs. non-ulcerated adjacent oral epithelial tissue of fasting RAS cases by immunohistochemistry. Specific Aim 3 (Ghrelin gene expression): We will conduct a pilot study to compare ghrelin and ghrelin receptors gene expression in ulcerated vs. non-ulcerated adjacent tissue of active RAS cases under fasting conditions using microarrays. Specific Aim 4 (Data/DNA Bank): Lastly, we will bank samples/DNA and epidemiologic data for future genetic epidemiologic studies aimed at understanding individual RAS susceptibility. The results of this research are crucial to advancing our understanding of RAS etiopathogenesis, and they are a necessary step toward the development of successful treatments targeted at the specific etiologic factor. Project Narrative: The goal of this research is to understand the cause of recurrent aphthous stomatitis (RAS, also known as canker sores) so that effective means of preventing and treating this condition may be developed and tested in future clinical trials. In particular, we are interested in knowing if patients with canker sores have a deficit of ghrelin (a newly discovered hormone involved in growth and mucosal protection from injury).