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.

项目摘要 我的长期职业目标是在一所大学里作为一名独立的调查员做假设驱动的研究 涵盖炎症性肠病（IBD）的基础和临床免疫学。为了实现这一目标，我 组建了一个由Matthew Olson博士（申办者）、Timothy Ratliff博士（共同申办者） 博士Tzu-wen Cross（合作者）、Majid Kazemian博士（合作者）、Shihuan Kuang博士和韦恩博士 坎贝尔提供技术培训，用于体外细胞培养技术，体内小鼠肠道模型 疾病，和gnotobiotic培训，以及其他专业发展技能的科学写作和 通信我在这份提案中概述的初步工作表明，具有常规T细胞的小鼠 两个重要的T细胞转录因子STAT 3和BATF的细胞特异性缺失， 自发性结肠炎，其特征是微生物群失调和γδ T细胞数量增加， 类似于在人类患者中观察到的情况。鉴于目前的治疗方案， IBD在长期治疗中并不完全有效，我的数据表明，通过阻断STAT 3/BATF轴， 靶向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。进一步 了解肠道微生物群失调与非常规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 肠道疾病期间的肠道γδ T细胞稳态。将使用16 S rRNA测序来确定 每种基因型小鼠的微生物群落。为了确定这种微生物群是否是必需的和足够的， 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 转移到无菌动物中。(2)确定γδ T细胞在驱动IBD中的作用。从治疗学上讲， 我将用单克隆抗体治疗小鼠，阻断γδ T细胞受体的激活，并监测其对 肠道炎症反应和临床疾病的发展。为了确定γδ T细胞 可以赋予疾病，我将从Stat 3fl/flBatffl/flCd 4Cre+小鼠中分离γδ T细胞并将其转移到结肠炎中 易感（Rag-/-）小鼠。这一提议的结果将进一步阐明γδ T细胞在 Stat 3fl/flBatffl/flCd 4Cre+小鼠，可作为研究IBD样结肠炎中γδ T细胞的有用模型。鉴于 目前IBD患者的治疗仅部分有效，本研究的结果数据和 在IBD样结肠炎中建立这种独特的γδ T细胞小鼠模型将潜在地鉴定新的治疗方法， 目标是对全球680万IBD患者产生积极影响。