Investigating the Role of IL-23R in Mucosal Regulatory T Cells

研究 IL-23R 在粘膜调节 T 细胞中的作用

基本信息

批准号：
10214607
负责人：
Jeremy Allen Goettel
金额：
$ 12.98万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214607
关键词：
Affect Alleles Antibodies Antigen-Presenting Cells Applications Grants Attenuated Automobile Driving Bacteria Biological Bone Marrow CD4 Positive T Lymphocytes Cause of Death Cell Respiration Cell physiology Cells Cellular Metabolic Process Cellular biology Cessation of life Chimera organism Chronic Clinical Colitis Colon Carcinoma Colorectal Cancer Complement Complex Crohn&apos s disease Data Data Set Dendritic Cells Disease Disease remission Disease susceptibility Enterobacteria phage P1 Cre recombinase Environmental Risk Factor Epigenetic Process Etiology Exhibits FOXP3 gene Frequencies Future Gastrointestinal tract structure Genetic Genetic Transcription Grant Homeostasis Human IL12B gene Immune Immune Tolerance Immune response Immune system Immunologic Factors Immunology Immunomodulators Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-12 Interleukin-17 Intestinal Diseases Intestines Investigation Knowledge Large Intestine Lesion Life Link LoxP-flanked allele Lymphocyte Lymphoid Cell Maintenance Malignant Neoplasms Mediating Mentored Research Scientist Development Award Mentors Metabolic Metabolic Pathway Metabolism Microbial Genetics Mitochondria Modeling Mucosal Immunity Mucous Membrane Mus Nature Nuclear Orphan Receptor Organ Pathogenesis Pathogenicity Pathway interactions Patients Phase III Clinical Trials Placebos Population Population Dynamics Postdoctoral Fellow Predisposition Production Prognosis Publishing Rectal Cancer Refractory Regulatory T-Lymphocyte Relapse Reporter Reporting Research Research Personnel Respiration Retinoic Acid Receptor Risk Role Signal Pathway Signal Transduction Site Source Superoxides T-Lymphocyte Therapeutic Transcript Ulcerative Colitis United States Variant Work carcinogenesis cell type cytokine disorder risk genome wide association study humanized mouse immunoregulation improved in vivo inflammatory disease of the intestine innovation interleukin-23 macrophage mouse model prevent programs promoter receptor receptor expression response single-cell RNA sequencing successful intervention systemic intervention therapeutically effective tumor

Affect Alleles Antibodies Antigen-Presenting Cells Applications Grants Attenuated Automobile Driving Bacteria Biological Bone Marrow CD4 Positive T Lymphocytes Cause of Death Cell Respiration Cell physiology Cells Cellular Metabolic Process Cellular biology Cessation of life Chimera organism Chronic Clinical Colitis Colon Carcinoma Colorectal Cancer Complement Complex Crohn&apos s disease Data Data Set Dendritic Cells Disease Disease remission Disease susceptibility Enterobacteria phage P1 Cre recombinase Environmental Risk Factor Epigenetic Process Etiology Exhibits FOXP3 gene Frequencies Future Gastrointestinal tract structure Genetic Genetic Transcription Grant Homeostasis Human IL12B gene Immune Immune Tolerance Immune response Immune system Immunologic Factors Immunology Immunomodulators Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-12 Interleukin-17 Intestinal Diseases Intestines Investigation Knowledge Large Intestine Lesion Life Link LoxP-flanked allele Lymphocyte Lymphoid Cell Maintenance Malignant Neoplasms Mediating Mentored Research Scientist Development Award Mentors Metabolic Metabolic Pathway Metabolism Microbial Genetics Mitochondria Modeling Mucosal Immunity Mucous Membrane Mus Nature Nuclear Orphan Receptor Organ Pathogenesis Pathogenicity Pathway interactions Patients Phase III Clinical Trials Placebos Population Population Dynamics Postdoctoral Fellow Predisposition Production Prognosis Publishing Rectal Cancer Refractory Regulatory T-Lymphocyte Relapse Reporter Reporting Research Research Personnel Respiration Retinoic Acid Receptor Risk Role Signal Pathway Signal Transduction Site Source Superoxides T-Lymphocyte Therapeutic Transcript Ulcerative Colitis United States Variant Work carcinogenesis cell type cytokine disorder risk genome wide association study humanized mouse immunoregulation improved in vivo inflammatory disease of the intestine innovation interleukin-23 macrophage mouse model prevent programs promoter receptor receptor expression response single-cell RNA sequencing successful intervention systemic intervention therapeutically effective tumor

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项目摘要

Project Summary Dysregulated immune responses to luminal bacteria in the intestine are largely responsible for the chronic nature of inflammatory bowel disease (IBD). Attenuating the inflammatory response via immunomodulators and/or biologics represent the majority of therapeutic strategies to induce remission. However, many patients either do not respond and those that initially do often stop responding. Restoring immune tolerance by increasing regulatory T cell (Treg) numbers or improving Treg function may be a viable strategy to achieve long-term remission. The PI’s K01 award has focused on strategies to expand Tregs in vivo to prevent experimental colitis in humanized mice. In the course of these studies, the cytokine interleukin-23 (IL-23) was upregulated in murine and human antigen presenting cells. Consistent with a role for IL-23 in IBD, variants in IL23R have been linked to IBD susceptibility. Furthermore, a recent phase 3 clinical trial in patients with Crohn’s disease targeted the p40 subunit of IL-23 (also shared with IL-12) and reported significant improvement in both induction and maintenance of clinical response and remission over placebo. Although macrophage and dendritic cells in the intestine are the source of IL-23, expression of IL-23R is generally restricted to lymphocytes and type 3 innate lymphoid cells (ILC3s). In this proposal, we will determine the role of IL-23R in Tregs in intestinal immune homeostasis and during inflammation using mice harboring floxed Il23r alleles combined with a Cre recombinase driven by the endogenous Foxp3 promotor. In Aim 1, we will determine the role of IL-23R in FOXP3+ Tregs during inflammation and inflammation-associated carcinogenesis. In Aim 2, we will define the transcriptional, metabolic, and signaling networks/pathways modulated by IL-23R signaling in intestinal FOXP3+ cells. Overall, these studies explore in detail how IL-23R differentially impacts mucosal immunity and it’s role during inflammation that will inform future therapeutic strategies for IBD and colon cancer. This proposal will further advance the independent studies of the PI and facilitate his transition as a successful investigator and leader in the field of mucosal immunology and will provide sufficient published and preliminary data to facilitate a highly competitive application for a R01 grant application as an early-stage investigator.

项目摘要肠中对腔细菌的免疫调查失调，主要是慢性的炎症性肠病（IBD）的性质。通过免疫调节剂减轻炎症反应和/或生物制剂代表了诱导缓解的大多数理论策略。但是，许多患者要么不回应，最初确实会停止回应的人。恢复免疫耐受性增加监管T细胞（TREG）数量或提高Treg功能可能是实现的可行策略长期缓解。 PI的K01奖的重点是在体内扩展Tregs的策略以防止人性化小鼠实验性结肠炎。在这些研究过程中，细胞因子白介素23（IL-23）是在鼠和人类抗原呈递细胞中上调。与IBD中IL-23的角色一致 IL23R与IBD易感性有关。此外，最近3阶段临床试验对患者克罗恩病针对IL-23的P40亚基（也与IL-12共享），并报告了显着安慰剂对临床反应和缓解的诱导和维持的改善。虽然肠道中的巨噬细胞和树突状细胞是IL-23的来源，IL-23R的表达通常为仅限于淋巴细胞和3型先天淋巴样细胞（ILC3S）。在此提案中，我们将确定角色肠道免疫稳态和炎症期间的Treg中的IL-23R的of使用含有Floxed IL23R的小鼠等位基因与内源性FOXP3启动子的CRE重组酶驱动相结合。在AIM 1中，我们将确定IL-23R在炎症和炎症相关期间IL-23R在FOXP3+ Treg中的作用致癌作用。在AIM 2中，我们将定义转录，代谢和信号网络/途径由IL-23R信号在肠道Foxp3+细胞中调节。总体而言，这些研究详细探讨了IL-23R如何差异影响粘膜免疫及其在炎症中的作用，这将为未来的治疗提供依据 IBD和结肠癌的策略。该提案将进一步推进PI和PI的独立研究促进他作为粘膜免疫学领域的成功调查员和领导者的过渡，并将提供足够的发布和初步数据，以促进R01赠款的竞争激烈的应用作为早期调查员的应用。