Control of Colitogenic Th17 cells by Vitamin D Receptor Signaling

项目总结 据估计，维生素D缺乏影响着全球超过10亿人，现在被认为是一个全球性的 健康危机。除了维持钙平衡和骨骼健康外，维生素D在 调节适应性免疫。低维生素D水平与各种免疫介导性疾病相关，包括 炎症性肠病(IBD)，而维生素D信号通过维生素D受体(VDR)被联系起来 为免疫耐受干杯。IBD发病的核心是促炎细胞Th17细胞的失调，Th17细胞是IBD的一个亚群 以产生白介素17A(IL-17A)为特征的CD4T细胞。虽然这些细胞通常 Th17细胞有助于粘膜屏障部位的动态平衡，是IBD的致病细胞。我们已经证明，VDR 在Th17分化过程中上调，维生素D治疗抑制Th17促炎因子的产生 细胞因子(如IL-17A)有利于免疫抑制细胞因子白介素10(IL-10)。维生素D如何治疗 调节Th17反应的机制尚不清楚。为了定义它的作用机制，我们生成了两个 具有VDR报告活性并对VDR配体有条件敲除的补充性小鼠模型 结合结构域(LBD)。根据我们的初步数据，我们认为VDR信号直接拮抗 Th17细胞中央转录因子RORgt对Th17发育的负性调节作用 功能--从而调节结肠炎的致病性。在这项提案中，我们将使用我们的新型转基因模型来 确定Th17群体中是否存在VDR表达的异质性以及是否存在配体结合 VDR是其限制Th17在结肠炎中致病作用的关键。提高我们对如何 这一途径可以调节Th17的功能，以预防免疫介导性疾病，如IBD 对患者肠道健康和治疗的广泛影响。 布莱克·弗雷的培训计划是由他的导师凯西·韦弗博士赞助的。的总目标是 培训计划是为PI作为一名成功的内科科学家职业生涯奠定坚实的基础。一个 这个项目与临床相关，同时专注于疾病发病的基本机制， 对于有抱负的内科科学家来说，这是一个理想的培训机会。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 布莱克了解环境因素对胃肠道免疫的临床影响 函数将使我们扩展对分子过程的理解和应用，以进一步 了解疾病并对患者进行个性化治疗。包括在培训计划中的经验将有助于 PI：1)掌握免疫遗传学和生物信息学相结合的各种技术；2) 发展以假设为导向的研究；3)以口头和书面形式展示数据；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.