Control of Colitogenic Th17 cells by Vitamin D Receptor Signaling

通过维生素 D 受体信号传导控制致结肠炎 Th17 细胞

• 批准号: 10155045
• 负责人: Blake Frey
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155045
• 关键词: Affect; Attention; Binding; Binding Sites; Bioinformatics; CD4 Positive T Lymphocytes; Calcium; Cells; Cholesterol; Clinic; Clinical; Clinical Trials; Colitis; Competence; DNA Binding; Data; Development; Disease; Enhancers; Environmental Risk Factor; Feedback; Foundations; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Goals; Health; Heterogeneity; Homeostasis; Hormones; IL17 gene; IL6 gene; IRF4 gene; Immune; Immune Tolerance; Immunogenetics; Impairment; Incidence; Industrialization; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-17; Interleukins; Intestines; Kinetics; Life Style; Ligand Binding; Ligand Binding Domain; Ligands; Link; Mediating; Mentors; Molecular; Mucous Membrane; Mus; Nuclear Receptors; Oral; Orphan; Pathogenesis; Pathogenicity; Pathway interactions; Patient Care; Patients; Physicians; Play; Population; Predisposition; Process; Production; RXR; Receptor Signaling; Regulator Genes; Reporter; Reporting; Research; Role; STAT3 gene; Scientist; Signal Transduction; Site; Societies; Solar Energy; Source; Specific qualifier value; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Transgenic Model; Ultraviolet B Radiation; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; adaptive immunity; base; bone health; career; clinically relevant; conditional knockout; cytokine; dietary; differential expression; disorder risk; experience; gastrointestinal; genome wide association study; genome-wide analysis; genomic locus; global health; immune function; improved; insight; mouse model; novel; prevent; receptor; receptor binding; receptor expression; recruit; response; responsible research conduct; skills; small molecule inhibitor; training opportunity; transcription factor

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.

项目概要 据估计，维生素 D (Vit D) 缺乏症影响着全球超过 10 亿人，现已被视为全球性问题 健康危机。除了维持钙稳态和骨骼健康外，维生素 D 在以下方面也发挥着重要作用： 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) 传递的维生素 D 信号传导也与此相关 达到免疫耐受。 IBD 发病机制的核心是促炎性 Th17 细胞（一个亚群）的失调 CD4 T 细胞的特征是产生白细胞介素 17A (IL-17A)。虽然这些细胞通常 Th17 细胞有助于粘膜屏障部位的稳态，因此在 IBD 中具有致病性。我们已经证明了 VDR 在 Th17 分化过程中上调，维生素 D 治疗可抑制 Th17 促炎物质的产生 细胞因子（例如 IL-17A）有利于免疫抑制细胞因子白细胞介素 10 (IL-10)。如何治疗维生素D 调节 Th17 反应尚不清楚。为了定义其作用机制，我们生成了两个 具有 VDR 报告基因活性并且是 VDR 配体条件性敲除的互补鼠模型 结合域（LBD）。根据我们的初步数据，我们建议 VDR 信号直接拮抗 Th17 细胞中央转录因子 RORgt 的活性，负向调节 Th17 发育和 功能——从而调节结肠炎的致病性。在本提案中，我们将使用我们的新颖转基因模型来 确定 Th17 群体内 VDR 表达是否存在异质性以及配体结合是否存在 VDR 对其限制 Th17 结肠炎致病性的作用至关重要。提高我们对如何进行的理解 该通路可以调节 Th17 功能以预防免疫介导的疾病，例如 IBD 对患者肠道健康和治疗产生广泛影响。 布莱克·弗雷 (Blake Frey) 拟议的培训计划由他的导师凯西·韦弗 (Casey Weaver) 博士赞助。总体目标为 培训计划旨在为 PI 提供作为医师科学家的成功职业生涯的坚实基础。一个 与临床相关的项目，同时关注疾病发病机制的基本机制， 对于有抱负的医生科学家来说，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至关重要。提供 布莱克（Blake）具有了解环境因素对胃肠道免疫的临床影响的技能 功能将使他能够扩展我们对分子过程的理解和应用，以进一步 了解疾病并个性化患者治疗。培训计划中包含的经验将有助于 PI：1）获得整合免疫遗传学和生物信息学的各种技术的能力； 2） 开展假设驱动的研究； 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。