A T cell STAT3/BATF-axis regulates intestinal γδ T cell homeostasis and disease

T 细胞 STAT3/BATF 轴调节肠道 γT 细胞稳态和疾病

• 批准号: 10752335
• 负责人: Nicole Anderson
• 金额: $ 3.92万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2025-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752335
• 关键词: 16S ribosomal RNA sequencing; Advisory Committees; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Automobile Driving; Blocking Antibodies; CD4 Positive T Lymphocytes; Case Study; Cell Communication; Cell Culture Techniques; Cell Surface Proteins; Cell physiology; Cells; Clinical; Clinical Immunology; Colitis; Colorectal Cancer; Communication; Complex; Data; Development; Disease; Disease Progression; Disease model; Exhibits; Functional disorder; Genetically Engineered Mouse; Genotype; Germ-Free; Gnotobiotic; Goals; Homeostasis; Human; Immune; Immune response; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Influentials; Interferon Type II; Interleukin-6; Intestinal Diseases; Intestines; Modeling; Monitor; Monoclonal Antibodies; Mus; Newly Diagnosed; Pathogenicity; Pathway interactions; Patients; Pattern; Persons; Play; Predisposition; Receptor Activation; Reporting; Research; Research Personnel; Role; STAT3 gene; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Spontaneous colitis; T cell response; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Trinitrobenzenesulfonic Acid; Universities; Work; Writing; career; cell type; cytokine; effective therapy; expectation; fecal microbiota; gut inflammation; gut microbiota; in vivo; interleukin-23; intestinal homeostasis; microbial community; microbiota; mouse model; new therapeutic target; novel; novel therapeutic intervention; prevent; response; skill acquisition; transcription factor; γδ T cells

PROJECT SUMMARY My long-term career goal is to do hypothesis-driven research as an independent investigator at a university spanning basic and clinical immunology in inflammatory bowel diseases (IBD). In order to achieve this goal, I have put together an advisory team composed of Dr. Matthew Olson (sponsor), Dr. Timothy Ratliff (co-sponsor), Dr. Tzu-wen Cross (collaborator), Dr. Majid Kazemian (collaborator), Dr. Shihuan Kuang, and Dr. Wayne Campbell to provide technical training for in vitro cell culture techniques, in vivo mouse models of intestinal disease, and gnotobiotic training, as well as other professional development skills in scientific writing and communication. My preliminary work outlined in this proposal has demonstrated that mice with conventional T cell-specific deletions in two important T cell transcription factors, STAT3 and BATF, developed an aggressive spontaneous colitis that was marked by a dysregulated microbiota and elevated numbers of γδ T cells in the intestines similar to what is observed in human patients. Given that the current treatment options available for IBD are not fully effective in long term treatment, my data indicate that disrupting this STAT3/BATF-axis through targeting the dysregulated gut microbiota or γδ T cells may represent a novel therapeutic strategy. To further understand this complex relationship between dysregulated gut microbiota and non-conventional γδ T cells in IBD-like colitis, this proposal will address the following: (1) Elucidate the role of the microbiota in regulating intestinal γδ T cell homeostasis during intestinal disease. 16S rRNA sequencing will be used to define shifts in the microbial community in each mouse genotype. To determine if this microbiota is required and sufficient to induce γδ T cell responses and disease we will treat animals with antibiotics and perform fecal microbiota transfers into germ-free animals, respectively. (2) Determine the role of γδ T cells in driving IBD. Therapeutically, I will treat mice with monoclonal antibodies that block γδ T cell receptor activation and monitor its impact on inflammatory responses in the intestines and clinical disease development. In order to determine if γδ T cells can confer disease, I will isolate γδ T cells from Stat3fl/flBatffl/flCd4Cre+ mice and transfer them into colitis susceptible (Rag-/-) mice. The results of this proposal will further elucidate the role of γδ T cells in Stat3fl/flBatffl/flCd4Cre+ mice, which may serve as useful model to study γδ T cells in IBD-like colitis. Given that current therapies for IBD patients are only partially effective, the resulting data from this study and the establishment of this unique mouse model of γδ T cells in IBD-like colitis will potentially identify novel therapeutic targets to make a positive impact on the 6.8 million people living with IBD worldwide.

项目概要 我的长期职业目标是作为大学的独立研究者进行假设驱动的研究 为了实现这一目标，我研究了炎症性肠病（IBD）的基础和临床免疫学。 组建了一个由 Matthew Olson 博士（发起人）、Timothy Ratliff 博士（共同发起人）组成的顾问团队， Tzu-wen Cross 博士（合作者）、Majid Kazemian 博士（合作者）、匡世焕博士、Wayne 博士 坎贝尔将为体外细胞培养技术、体内小鼠肠道模型提供技术培训 疾病和生殖培训，以及科学写作和其他方面的专业发展技能 我在本提案中概述的初步工作表明，具有传统 T 的小鼠 两种重要的 T 细胞转录因子 STAT3 和 BATF 的细胞特异性缺失，形成了一种侵袭性的 自发性结肠炎，其特征是肠道菌群失调和 γδ T 细胞数量增加 鉴于目前可用的治疗方案，肠道与在人类患者中观察到的情况相似。 IBD 在长期治疗中并不完全有效，我的数据表明，通过破坏此 STAT3/BATF 轴 针对失调的肠道微生物群或 γδ T 细胞可能代表一种新的治疗策略。 了解失调的肠道微生物群与非常规 γδ T 细胞之间的复杂关系 IBD 样结肠炎，该提案将解决以下问题：（1）阐明微生物群在调节中的作用 16S rRNA 测序将用于定义肠道疾病期间肠道 γδ T 细胞稳态的变化。 每种小鼠基因型中的微生物群落，以确定该微生物群是否是必需的并且足以 诱导 γδ T 细胞反应和疾病 我们将用抗生素治疗动物并进行粪便微生物群分析 (2) 确定 γδ T 细胞在治疗 IBD 中的作用。 我将用单克隆抗体治疗小鼠，阻断 γδ T 细胞受体激活并监测其对 肠道炎症反应和临床疾病发展以确定 γδ T 细胞是否存在。 可以赋予疾病，我将从 Stat3fl/flBatffl/flCd4Cre+ 小鼠中分离 γδ T 细胞并将其转移到结肠炎中 该提案的结果将进一步阐明 γδ T 细胞在易感 (Rag-/-) 小鼠中的作用。 Stat3fl/flBatffl/flCd4Cre+ 小鼠，这可能作为研究 IBD 样结肠炎中 γδ T 细胞的有用模型。 目前对 IBD 患者的治疗仅部分有效，本研究的结果数据和 建立这种独特的 IBD 样结肠炎 γδ T 细胞小鼠模型将有可能确定新的治疗方法 目标是对全球 680 万 IBD 患者产生积极影响。