Control of Colitogenic Th17 cells by Vitamin D Receptor Signaling

项目摘要 据估计，维生素D缺乏症影响全球超过10亿人，现在被认为是全球性的疾病。 健康危机。除了维持钙稳态和骨骼健康外，维生素D还在以下方面发挥重要作用： 调节适应性免疫低维生素D水平与各种免疫介导的疾病相关，包括 炎症性肠病（IBD），而通过维生素D受体（VDR）的维生素D信号传导与 免疫耐受IBD发病机制的核心是促炎性Th 17细胞的失调， CD 4 T细胞的特征在于其产生白细胞介素-17A（IL-17 A）。虽然这些细胞通常 由于Th 17细胞有助于粘膜屏障部位的稳态，所以Th 17细胞在IBD中是致病性的。我们已经证明，VDR 在Th 17分化过程中上调，用维生素D治疗可抑制Th 17产生促炎性细胞因子。 细胞因子（例如，IL-17 A），有利于免疫抑制细胞因子白细胞介素-10（IL-10）。维生素D治疗 调节Th 17应答的机制尚不清楚。为了确定其作用机制，我们生成了两个 具有VDR报告基因活性并且是VDR配体的条件性敲除的互补鼠模型 结合结构域（LBD）。基于我们的初步数据，我们提出VDR信号直接拮抗 Th 17细胞的中心转录因子RORgt负调节Th 17发育的活性， 功能-从而调节结肠炎致病性。在这项提议中，我们将使用我们的新型转基因模型， 确定在Th 17群体内是否存在VDR表达的异质性，以及是否存在配体结合 VDR对限制结肠炎中Th 17致病性的作用至关重要。提高我们对 该途径可以调节Th 17功能以保护免受免疫介导的疾病，如IBD， 对患者肠道健康和治疗具有广泛的意义。 布莱克·弗雷的训练计划是由他的导师凯西·韦弗博士赞助的。的总目标 培训计划是为PI作为一名医生-科学家的成功职业生涯提供坚实的基础。一 该项目是临床相关的，同时侧重于疾病发病机制的基本机制， 是一个理想的培训机会，为有抱负的医生，科学家。随着分子信息变得 对于患者护理来说，理解和解释这些类型的数据的能力将是必不可少的。提供 布莱克用技巧了解临床环境因素对胃肠免疫的影响 功能将使他能够扩展我们对分子过程的理解和应用， 了解疾病和个性化的患者治疗。培训计划中包括的经验将有助于 PI：1）获得整合免疫遗传学和生物信息学各种技术的能力; 2） 发展假设驱动的研究; 3）以口头和书面形式呈现数据; 4）有效整合 研究和临床; 5）与其他科学家合作; 6）负责任地进行研究。

PROJECT SUMMARY Vitamin D (Vit D) deficiency is estimated to affect over 1 billion people worldwide and is now considered a global health crisis. In addition to maintaining calcium homeostasis and bone health, Vit D plays an important role in regulating adaptive immunity. Low Vit D levels correlate with various immune-mediated diseases, including inflammatory bowel disease (IBD), while Vit D signaling through the vitamin D receptor (VDR) has been linked to immune tolerance. Central to IBD pathogenesis is the dysregulation of proinflammatory Th17 cells, a subset of CD4 T cells that are characterized by their production of interleukin-17A (IL-17A). While these cells normally contribute to homeostasis at mucosal barrier sites, Th17 cells are pathogenic in IBD. We have shown that VDR is upregulated during Th17 differentiation and treatment with Vit D inhibits Th17 production of proinflammatory cytokines (e.g., IL-17A) in favor of the immunosuppressive cytokine, interleukin-10 (IL-10). How Vit D treatment modulates the Th17 response is unclear. To define its mechanism of action, we have generated two complementary murine models that have VDR reporter activity and are conditional knockouts for the VDR ligand binding domain (LBD). Based on our preliminary data, we propose that VDR signaling directly antagonizes activity of the central transcription factor of Th17 cells, RORgt, to negatively regulate Th17 development and function—thereby modulating colitis pathogenicity. In this proposal, we will use our novel transgenic models to determine whether there is heterogeneity of VDR expression within Th17 populations and whether ligand binding by VDR is essential for its actions in limiting Th17 pathogenicity in colitis. Improving our understanding of how this pathway can modulate Th17 function to protect against immune-mediated diseases, such as IBD, will have broad-reaching implications on patient intestinal health and therapy. The proposed training plan for Blake Frey is sponsored by his mentor, Dr. Casey Weaver. The overall goal of the training plan is to provide the PI with a strong foundation for a successful career as a physician-scientist. A project that is clinically relevant, while focused on a fundamental mechanism of disease pathogenesis, represents the ideal training opportunity for an aspiring physician-scientist. As molecular information becomes more integral to patient care, the ability to understand and interpret these types of data will be essential. Providing Blake with the skills to understand the clinical influence of environmental factors on gastrointestinal immune function will enable him to expand our understanding and application of molecular processes to further understand disease and personalize patient therapy. Included in the training plan are experiences that will help the PI: 1) gain competence in a variety of techniques that integrate immunogenetics and bioinformatics; 2) develop hypothesis-driven research; 3) present data in an oral and written format; 4) effectively integrate research and the clinic; 5) collaborate with other scientists; and 6) responsibly conduct research.