Molecular mechanisms contributing to gender differences in regulatory T cell function in Crohn's disease and experimental IBD



 DESCRIPTION (provided by applicant): Crohn's disease (CD) represents a significant public health challenge. Pathogenesis is promoted by chronic inflammation of the intestinal mucosa, resulting in loss of tolerance to exogenous factors such as microbial and dietary antigens. There is an increased incidence of CD among female patients, who also experience worse clinical symptoms compared to males. Genetic and environmental factors such as the ovarian hormone 17-β-estradiol (estrogen, E2) have been identified as risk factors for CD, given the frequent onset of females' CD during puberty, as well as females' worsening symptoms during times of elevated E2 levels. Recent exciting studies from our group demonstrated that E2-mediated signaling is impaired in T cells isolated from female ileitis-prone mice. This is in contrast to th effects of E2 signaling under non-pathological conditions, in which E2 induces conversion of conventional T cells (Tconv) to regulatory T cells Treg, thus enhancing immune protection. Thus, there is a need for mechanistic studies aimed at delineating the molecular mechanisms by which E2 may result in exacerbated CD. Studies proposed herein take advantage of a unique resource, a spontaneous murine model of Crohn's-like ileitis (SAMP1/YitFc (SAMP)), to clarify the mechanistic role of E2 signaling in experimental ileitis. Our group has recently shown that SAMP mice recapitulate several key aspects of human CD, including Treg dysfunction (Ishikawa et al, Mucosal Immunol 2013) and female sex bias (Goodman et al, Mucosal Immunol 2014). Specifically, we recently showed that Tregs isolated from female SAMP (SAMP-F) exhibit impaired suppressive function in vivo and reduced expression of key Treg-associated genes such as foxp3 and helios. Following treatment with exogenous E2, SAMP-M expand their mucosal Treg pool and demonstrate improvement in ileitis, whereas SAMP-F do not expand their Tregs and do not improve clinically. In exciting new data generated since the first submission, we have shown that gene expression of estrogen receptor beta (ERβ) is markedly upregulated in SAMP-F T cells, and that deletion of ERβ results in clinical improvement and a restoration of Treg function in SAMP-F mice. These novel observations serve as the basis for the central hypothesis that dysfunctional E2/ERβ signaling predicates female sex bias in SAMP, despite females' higher circulating levels of E2. The goals of this proposal are: (1) To demonstrate that dysregulated ERβ signaling contributes to worsened SAMP-F ileitis; and (2) to identify the molecular mechanism(s) responsible for dysfunctional Treg responses in SAMP-F. The successful completion of these aims will provide key knowledge about E2-dependent mechanism(s) for female sex bias in IBD. Given the immunoprotective role of E2 under non-pathological conditions, understanding the mechanisms by which E2 signaling may be subverted in female CD patients is essential for development of novel therapies designed to function effectively in different hormonal environments and for future efforts towards individualized care. The candidate's long-term career goals include the development of an independent research program in the scientific area of molecular control of lymphocyte function in IBD. She has extensive training in the pathogenesis of autoimmune disease, having authored three first-author research papers in this area and several reviews (see attached Candidate Biosketch). A rigorous Career Development Plan has been developed (see attached documents) which includes didactic coursework, participation in numerous research seminar series, training in the responsible conduct of research, and regular meetings with her Scientific Advisory Committee. The sponsor, Dr. Theresa Pizarro, is a well- established investigator in the field of IBD with a strong record of funding and mentorship. Dr. Pizarro, along with the Department of Pathology at Case Western Reserve University, have committed fully to supporting the candidate as she transitions to a fully independent research faculty position. Dr. Goodman will be promoted to the Faculty rank of Instructor within the 2014-2015 academic year, allowing her to compete for R-series grants that will derive from data and hypotheses generated in the current K01 proposal.