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（由适用提供）：克罗恩病（CD）代表了重大的公共卫生挑战。发病机理是通过肠道粘膜的慢性炎症来促进的，从而导致对外源性因子（例如微生物和饮食抗原）的耐受性丧失。女性患者的CD发病率增加，与男性相比，临床症状也更糟糕。鉴于青春期中女性的CD经常发作，以及在E2升高时期，雌性CD经常发作，而女性的症状经常出现，遗传和环境因素（例如卵巢果子17-β-雌二醇（雌激素，E2））被确定为CD的危险因素。我们小组的最新令人兴奋的研究表明，从雌性易肝炎的小鼠分离的T细胞中E2介导的信号传导受损。这与在非病理条件下E2信号传导的影响相反，在非病理条件下，E2诱导常规T细胞（TCONV）的转化以调节T细胞Treg，从而增强免疫保护。这是需要进行机械研究，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独特的资源，这是克罗恩斯样肠炎的赞助鼠模型（SAMP1/YITFC（SAMP）），以阐明E2信号在实验性卵巢炎中的机械作用。我们的小组最近表明，SAMP小鼠概括了人CD的几个关键方面，包括Treg功能障碍（Ishikawa等，Mucosal Immunol，2013）和女性性偏见（Goodman等，MicaL Immunol 2014）。具体而言，我们最近表明，从雌性SAMP（SAMP-F）裸露的抑制功能中分离出的TREG在体内抑制功能受损，并在用外源E2处理后与Treg相关基因的关键基因表达降低，SAMP-M扩大了粘膜Treg池并显示出肌炎的粘膜treg池，而肌炎的症状不断提高，而samp-f则不能扩大treg和tregs的提高和诊所的诊所。在自第一次提交以来产生的令人兴奋的新数据中，我们表明，雌激素受体β（ERβ）的基因表达在SAMP-F T细胞中显着更新，并且ERβ的缺失导致SAMP-F-F小鼠中Treg功能的临床改善和恢复。这些新颖的观察结果是中心假设的基础，即功能失调的E2/ERβ信号传导可预测女性所需的女性E2较高循环水平的女性性偏见。该提案的目标是：（1）证明ERβ信号失调会导致SAMP-FILESITIS恶化； （2）确定负责SAMP-F中功能障碍Treg响应的分子机制。这些目标的成功完成将提供有关IBD女性性偏见E2依赖机制的关键知识。鉴于E2在非病理条件下的免疫保护作用，了解女性CD患者中E2信号传导的机制对于开发旨在在不同的激素环境中有效发挥作用的新型疗法以及对个性化护理的未来努力至关重要。候选人的长期职业目标包括在IBD中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理方面进行了广泛的培训，在该领域撰写了三份第一名研究论文，并进行了几次评论（请参阅附带的候选Biosketch）。已经制定了一项严格的职业发展计划（请参阅附件文档），其中包括教学课程，参加众多研究精神系列，负责研究的培训以及与她的科学咨询委员会的定期会议。赞助商特蕾莎·皮萨罗（Theresa Pizarro）博士是IBD领域的一名成熟的研究员，并具有丰富的资金和心态记录。 Pizarro博士以及Case Western Reserve University的病理学系也完全致力于支持候选人。当她过渡到完全独立的研究教师时。古德曼博士将在2014-2015学年中晋升为教师等级，使她能够竞争R系列赠款，这些赠款将从当前K01提案中产生的数据和假设获得。