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: 9146962
• 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/9146962
• 关键词: Adoptive Transfer; Advisory Committees; Agonist; Antigens; Area; Autoimmune Diseases; Autoimmunity; Backcrossings; Binding; Biological Assay; Caring; 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; Faculty; Female; Flare; Frequencies; Functional disorder; Funding; Future; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Grant; Health; Hormonal; Human; IL2RA gene; Ileitis; Immune; Immunoprecipitation; In Vitro; Incidence; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Intrinsic factor; Knockout Mice; Knowledge; Lymphocyte Function; Mediating; Mentorship; Messenger RNA; Modeling; Molecular; 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; Signal Transduction; Symptoms; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Training; Universities; Up-Regulation; Wild Type Mouse; base; career; career development; chromatin immunoprecipitation; design; experience; 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; research study; response; responsible research conduct; restoration; sex; 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（由申请方提供）：克罗恩病（CD）是一项重大的公共卫生挑战。发病机制由肠粘膜的慢性炎症促进，导致对外源性因素如微生物和饮食抗原的耐受性丧失。女性患者中CD的发病率增加，与男性相比，女性患者的临床症状也更差。遗传和环境因素，如卵巢激素17-β-雌二醇（雌激素，E2）已被确定为CD的风险因素，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，E2介导的信号在从雌性回肠炎易感小鼠分离的T细胞中受损。这与E2信号传导在非病理条件下的作用相反，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，旨在描绘E2可能导致CD恶化的分子机制。 本文提出的研究利用独特的资源，克罗恩氏样回肠炎的自发小鼠模型（SAMP 1/YitFc（SAMP）），以澄清E2信号传导在实验性回肠炎中的机制作用。我们的小组最近已经表明，SAMP小鼠重现了人CD的几个关键方面，包括Treg功能障碍（石川等人，Muclidin Immunol 2013）和女性性别偏见（Goodman等人，Muclidin Immunol 2014）。具体来说，我们最近发现，从女性SAMP（SAMP-F）中分离的Treg在体内表现出受损的抑制功能，并降低了关键Treg相关基因（如foxp 3和helios）的表达。在用外源性E2治疗后，SAMP-M扩增其粘膜Treg库并显示回肠炎的改善，而SAMP-F不扩增其Treg库并且在临床上不改善。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的缺失导致临床改善和SAMP-F小鼠Treg功能的恢复。这些新的观察结果作为核心假设的基础，即功能失调的E2/ERβ信号转导预示着SAMP中的女性性别偏见，尽管女性的E2循环水平较高。本提案的目的是：（1）证明ERβ信号转导失调导致SAMP-F回肠炎恶化;（2）鉴定SAMP-F中Treg应答功能失调的分子机制。这些目标的成功完成将为IBD中女性性别偏见的E2依赖机制提供关键知识。考虑到E2在非病理条件下的免疫保护作用，了解E2信号传导在女性CD患者中可能被颠覆的机制对于开发旨在在不同激素环境中有效发挥作用的新型疗法以及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，在该领域撰写了三篇第一作者研究论文和几篇综述（见随附的候选人Biosketch）。制定了严格的职业发展计划（见所附文件），其中包括教学课程、参加许多研究研讨会系列、负责任地开展研究方面的培训以及与她的科学咨询委员会定期举行会议。申办者Theresa Pizarro博士是IBD领域的知名研究者，在资助和指导方面有着良好的记录。Pizarro博士，沿着凯斯西储大学病理学系，致力于全力支持候选人，因为她过渡到一个完全独立的研究教师职位。古德曼博士将在2014-2015学年晋升为教员，使她能够竞争R系列赠款，这些赠款将来自当前K 01提案中产生的数据和假设。