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

克罗恩病和实验性 IBD 调节性 T 细胞功能性别差异的分子机制

• 批准号: 9750684
• 负责人: Wendy Ann Goodman
• 金额: $ 11.3万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750684
• 关键词: Adoptive Transfer; Advisory Committees; Agonist; Antigens; Area; Autoimmune Diseases; Autoimmunity; Backcrossings; Biological Assay; Cell physiology; Cells; Chronic; Clinical; Complex; Coupled; Crohn' s disease; Data; Defect; Development; Development Plans; Diet; Environment; Environmental Risk Factor; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Estrous Cycle; Exhibits; Exogenous Factors; FOXP3 gene; Faculty; Female; Flare; Frequencies; Functional disorder; Funding; Future; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Grant; Hormonal; Human; IL2RA gene; Ileitis; Immune; Immunoprecipitation; Impairment; In Vitro; Incidence; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Intrinsic factor; Knockout Mice; Knowledge; Lymphocyte Function; Mediating; Mentorship; Messenger RNA; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Oral Contraceptives; Outcome; Outcome Measure; Ovarian hormone; Paper; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Positioning Attribute; Protein Isoforms; Proteins; Puberty; Public Health; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Resistance; Resources; Risk Factors; Role; Series; Serum; Sex Bias; Sex Differences; Signal Transduction; Symptoms; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Training; Universities; Up-Regulation; Wild Type Mouse; career; career development; chromatin immunoprecipitation; design; effector T cell; experience; experimental study; faculty research; gender difference; health related quality of life; improved; in vivo; instructor; male; meetings; microbial; mouse model; next generation; novel; novel therapeutics; personalized care; programs; public health relevance; response; responsible research conduct; restoration; steroid hormone; therapy design; transcription factor; transcriptome sequencing; treatment strategy

 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.

 描述(由申请人提供)：克罗恩病(CD)是一个重大的公共卫生挑战。发病机制是由肠道粘膜的慢性炎症促进的，导致对微生物和饮食抗原等外部因素的耐受性丧失。CD在女性患者中的发病率增加，她们的临床症状也比男性更严重。遗传和环境因素，如卵巢激素17-雌二醇(β，E2)，已被确定为CD的危险因素，因为女性CD在青春期频繁发作，以及女性在E2水平升高期间症状恶化。我们小组最近令人兴奋的研究表明，从易患回肠炎的雌性小鼠分离的T细胞中，E2介导的信号转导受到损害。这与在非病理条件下E2信号的作用相反，在非病理条件下，E2诱导常规T细胞(Tconv)转化为调节性T细胞Treg，从而增强免疫保护。因此，有必要进行机制研究，以描述E2可能导致CD加重的分子机制。本文提出的研究利用了一种独特的资源，即自发的克罗恩样回肠炎小鼠模型(SAMP1/YitFc(SAMP))，以阐明E2信号在实验性回肠炎中的机制作用。我们的小组最近表明，SAMP小鼠概括了人类CD的几个关键方面，包括Treg功能障碍(Ishikawa等人，Mucosal Invol 2013)和女性性别偏见(Goodman等人，Mucosal Invol 2014)。具体地说，我们最近发现从女性SAMP(SAMP-F)中分离出的Treg在体内表现出抑制功能受损，以及关键的Treg相关基因如Foxp3和Helios的表达减少。在外源性E2治疗后，SAMP-M扩大了他们的粘膜Treg池，并显示回肠炎的改善，而SAMP-F没有扩大他们的Treg，临床上也没有改善。在首次提交以来产生的令人兴奋的新数据中，我们已经表明雌激素受体β(ERβ)的基因表达在SAMP-F T细胞中显著上调，并且ERβ的缺失导致SAMP-F小鼠的临床改善和Treg功能的恢复。这些新的观察结果作为中心假设的基础，即尽管女性循环中的E2水平较高，但E2/ERβ信号功能障碍预示着SAMP中的女性性别偏见。这项建议的目的是：(1)证明ERβ信号通路的失调有助于SAMP-F回肠炎的恶化；(2)确定SAMP-F功能紊乱的Treg反应的分子机制(S)。这些目标的成功实现将为了解女性IBD性别偏见的雌激素依赖机制(S)提供关键知识。鉴于E2在非病理条件下的免疫保护作用，了解在女性CD患者中E2信号可能被颠覆的机制对于开发在不同荷尔蒙环境中有效发挥作用的新疗法和未来个性化护理的努力至关重要。候选人的长期职业目标包括在IBD淋巴细胞功能的分子控制科学领域开发一项独立的研究计划。她在自身免疫性疾病的发病机制方面接受了广泛的培训，在这一领域撰写了三篇第一作者研究论文和几篇评论(见所附的候选生物素描)。已经制定了严格的职业发展计划(见附件)，其中包括授课、参加许多系列研究研讨会、负责任地进行研究方面的培训，以及与她的科学咨询委员会的定期会议。赞助商Theresa Pizarro博士是IBD领域的一位知名研究员，在资金和指导方面有着良好的记录。皮萨罗博士和凯斯西储大学病理学系已经承诺全力支持这位候选人在她过渡到一个完全独立的研究教授职位的过程中。古德曼博士将在2014-2015学年内晋升为讲师，这将使她能够竞争R系列补助金，这些补助金将来自当前K01提案中产生的数据和假设。