Dissecting the role of GPR34 in cDC1 migration and function

剖析 GPR34 在 cDC1 迁移和功能中的作用

基本信息

批准号：
10748747
负责人：
Hanson Peter Tam
金额：
$ 3.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748747
关键词：
Antigen Presentation Antigens Area Biological Assay Biological Models Biology Bone Marrow CD8-Positive T-Lymphocytes California Cell Communication Cell physiology Cells Cellular Assay Chemotactic Factors Chimera organism Clinical Collaborations Colon Adenocarcinoma Colon Carcinoma Colorectal Cancer Confocal Microscopy Cross Presentation Data Dendritic Cells Educational workshop Engineering Environment Enzymes Epithelial ovarian cancer Flow Cytometry G-Protein-Coupled Receptors Generations Goals Greater sac of peritoneum Growth Immune Immune response Immunity Immunofluorescence Immunologic Immunofluorescence Microscopy Immunology Implant In Vitro Infection Inflammation Journals Kinetics Ligands Link Liquid substance Lymphoid Tissue MC38 Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Mediator Mentorship Microanatomy Migration Assay Modeling Mus Natural Immunity Neoplasm Metastasis Organ Outcome Ovalbumin Peritoneal Peritonitis Phenotype Physicians Physiology Positioning Attribute Postdoctoral Fellow Process Proliferating Qualifying Reporting Research Role San Francisco Scientist Shapes Signal Transduction Site Source Supporting Cell System T cell response T-Lymphocyte Techniques Testing Therapeutic Thioglycolates Time Training Tumor Cell Line Tumor Immunity Universities Visualization Vocational Education Weight Work XCR1 gene adaptive immunity antigen-specific T cells cancer cell career cell motility cell type clinical training colon cancer metastasis druggable target experimental study in vivo innovation lysophosphatidylserine medical schools migration overexpression pathogen receptor recruit response skills subcutaneous symposium therapeutic development tool trafficking tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT As critical mediators of immunity against intracellular pathogens and cancer, type 1 conventional dendritic cells (cDC1s) cross-present exogenous, cell-associated antigens to CD8+ T cells, facilitated by the colocalization of these two cell types in the T cell zone of secondary lymphoid tissues. This microanatomical organization is orchestrated by CCR7 and XCR1, two G protein-coupled receptors (GPCRs) on cDC1s that guide their migration towards gradients of chemoattractant ligand. Recent reports have established a crucial role for tumor-associated cDC1s in cancer immunity. However, the GPCRs mediating cDC1 recruitment and positioning at sites of inflammation and in tumors are incompletely understood. Preliminary work has revealed that GPR34, an understudied X-linked GPCR, is highly expressed by cDC1s, and in vitro studies have shown that this lysophosphatidylserine (lysoPS)-responsive receptor supports cell migration. Preliminary data presented herein indicate that GPR34 promotes the accumulation of cDC1s in the inflamed mouse peritoneal cavity (PerC) in a cell-intrinsic manner. The PerC is a clinically important site for colon and ovarian cancer metastasis. In a preliminary experiment inspired by the connection between cDC1 accumulation and cancer outcomes, GPR34-deficiency led to increased growth of a subcutaneous (SQ) tumor model. This proposal will test the hypothesis that GPR34 regulates cDC1 organization and function during inflammation and cancer. Aim 1 will mechanistically define how GPR34 controls the abundance, trafficking, and positioning of PerC cDC1s using a combination of techniques including in vivo kinetic immune phenotyping, in vitro migration assays, and immunofluorescence microscopy. Aim 2 will investigate the role of GPR34 and lysoPS in cancer immunity using ectopic SQ and PerC tumor models along with tools to study antigen-specific T cell responses and to manipulate ligand levels. Completion of these Aims will elucidate key mechanisms by which GPR34 on cDC1s influences the response to inflammation and malignancy, providing opportunities for the development of therapeutics that modulate the lysoPS-GPR34 chemoattractant system. These research goals will be conducted in conjunction with a comprehensive training plan to prepare the applicant for an independent career as an academic physician-scientist. Training includes rigorous mentorship in scientific skills from a highly qualified sponsor, Dr. Jason Cyster; technical education from postdoctoral fellows in the applicant’s lab and collaborating labs; seminars, journal clubs, workshops, and conferences; and clinically geared activities. Research and training will take place at the University of California, San Francisco, which offers a highly innovative and collaborative immunology research environment and an exceptional medical school for clinical training.

项目概要/摘要作为针对细胞内病原体和癌症的免疫的关键介质，1 型常规树突状细胞 (cDC1s) 将外源细胞相关抗原交叉呈递给 CD8+ T 细胞，这是由这两种细胞类型共定位于次级淋巴组织的 T 细胞区。该组织由 CCR7 和 XCR1 精心策划，这两个位于 cDC1 上的 G 蛋白偶联受体 (GPCR) 引导它们向趋化剂配体的梯度迁移最近的报告已经建立了一个关键的方法。肿瘤相关的 cDC1 在癌症免疫中的作用然而，GPCR 介导 cDC1 募集和在炎症部位和肿瘤中的定位尚不完全清楚。初步研究表明，GPR34 是一种尚未研究的 X 连锁 GPCR，在 cDC1 和体外研究表明，这种溶血磷脂酰丝氨酸 (lysoPS) 反应性受体支持本文提供的初步数据表明 GPR34 促进 cDC1 的积累。以细胞内在方式观察发炎的小鼠腹膜腔 (PerC) PerC 是临床上重要的部位。受 cDC1 之间联系启发的一项初步实验。 GPR34 缺陷导致皮下 (SQ) 肿瘤生长加快该模型将检验 GPR34 调节 cDC1 组织和功能的假设。目标 1 将机械地定义 GPR34 如何控制丰度，使用包括体内动态免疫在内的技术组合来运输和定位 PerC CDC1 表型分析、体外迁移和免疫荧光显微镜检查将研究其作用。使用异位 SQ 和 PerC 肿瘤模型以及研究工具研究 GPR34 和 lysoPS 在癌症免疫中的作用抗原特异性 T 细胞反应和操纵配体水平的完成将阐明关键。 cDC1 上的 GPR34 影响炎症和恶性肿瘤反应的机制，提供开发调节 lysoPS-GPR34 趋化系统的疗法的机会。这些研究目标将与全面的培训计划一起进行，以做好准备作为学术医师科学家的独立职业的申请人需要接受严格的培训。来自高素质赞助商 Jason Cyster 博士的科学技能指导；申请人实验室和合作实验室的博士后研究员；会议；以及临床相关的活动将在大学进行。加利福尼亚州、旧金山，提供高度创新和协作的免疫学研究环境以及一所提供临床培训的杰出医学院。