Role of immune cell OGR1 in prostate cancer development and the mechanisms involv

免疫细胞OGR1在前列腺癌发生发展中的作用及其机制

• 批准号: 8296495
• 负责人: YAN XU
• 金额: $ 42.08万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296495
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Agonist; B-Lymphocytes; Bone Marrow; CD8B1 gene; Cancer Etiology; Cell Lineage; Cell physiology; Cells; Cessation of life; Conditioned Culture Media; Data; Development; Effector Cell; Foundations; Future; G-Protein-Coupled Receptors; GPR68 gene; Genes; Goals; Human; ITGAM gene; Immune; Immune response; Immunotherapy; In Vitro; Incidence; Infiltration; Knockout Mice; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Myelogenous; Natural Killer Cells; Neoplasm Metastasis; Nude Mice; Physiological; Play; Population; Principal Investigator; Reporting; Role; Signal Transduction; Structure of base of prostate; Suppressor-Effector T-Lymphocytes; System; T-Cell Depletion; T-Lymphocyte; Testing; Time; Transplantation; United States; Up-Regulation; Wild Type Mouse; arginase; base; cancer cell; cancer immunotherapy; cell type; human TGFB1 protein; in vivo; macrophage; men; mouse model; neoplastic cell; novel; programs; research study; tumor; tumor immunology; tumorigenesis

DESCRIPTION (provided by applicant): We previously cloned a G protein coupled receptor termed OGR1 from cancer cells and generated OGR1 knockout mice (ogr1-/-). Our substantial preliminary data suggest that OGR1 plays crucial roles in immune cells, and in T cells and Gr1 and CD11b double positive (DP+) cells in particular. We hypothesize that OGR1 expression not only affects the numbers of DP+ cells, but also their functions after prostate cancer (PCa) tumor cell challenge; and DP+ cells are the major suppressor cells and T cells are the major effector cells for OGR1-depedent effects in PCa. These concepts will be tested in three Specific Aims. The main goal of this proposal is to determine the cellular and molecular mechanisms underlying the functions of OGR1 in immune cells pertinent to its role in PCa tumorigenesis and metastasis. Aim 1. Investigate the role of OGR1 in T cells in PCa tumorigenesis and metastasis by 1) determining the functions of OGR1 in T cells in vivo using T cells depletion and adoptive transfer mice; by 2) examining the effect of OGR1 depletion in specific T cell lineages using specific Cre-Lox systems in mice; and by 3) determining the time course of T cell infiltration and tumor cell eradication in ogr1-/- mice. Aim 2. Determine the role of OGR1 in Gr1 and CD11b double positive (DP+) cells in PCa tumorigenesis and metastasis by 1) determining OGR1 expression in which immune cell populations is functionally involved and required for tumor development; by 2) determining the role of OGR1 in myeloid lineage in PCa development using LysM Cre-mice; and by 3) testing whether the OGR1 effects on tumorigenesis and DP+ cells are restricted to certain cancer cells. Aim 3. Delineate molecular mechanisms underlying OGR1's role in T and DP+ cells. 1) Investigate the signaling mechanisms by which OGR1 regulates the arginase activity in DP+ cells. 2) Elucidate the mechanisms by which the TRAMP-C2 conditioned medium and/or TGF-beta1 induce up-regulation of OGR1 in immune cells. 3) Test the effects of OGR1-specific agonists/antagonists in immune cells and in vivo. 4) Determine the structural requirement in OGR1 for its functions. Our long-term goal is to develop OGR1-based novel immunotherapy for cancers.

描述（由申请人提供）：我们先前从癌细胞克隆了称为OGR 1的G蛋白偶联受体，并产生了OGR 1敲除小鼠（ogr 1-/-）。 我们大量的初步数据表明，OGR 1在免疫细胞中起着至关重要的作用，特别是在T细胞和Gr 1和CD 11b双阳性（DP+）细胞中。 我们假设OGR 1的表达不仅影响DP+细胞的数量，而且还影响它们在前列腺癌（PCa）肿瘤细胞攻击后的功能;并且DP+细胞是PCa中OGR 1依赖性效应的主要抑制细胞，T细胞是主要效应细胞。 这些概念将在三个具体目标中得到检验。 该建议的主要目标是确定OGR 1在免疫细胞中功能的细胞和分子机制，这些功能与其在PCa肿瘤发生和转移中的作用有关。 目标1.通过以下方式研究T细胞中OGR 1在PCa肿瘤发生和转移中的作用：1）使用T细胞耗竭和过继转移小鼠在体内确定T细胞中OGR 1的功能; 2）使用特定Cre-Lox系统在小鼠中检查特定T细胞谱系中OGR 1耗竭的作用; 3）确定ogr 1-/-小鼠中T细胞浸润和肿瘤细胞根除的时间过程。 目标2.通过1）确定OGR 1表达，其中免疫细胞群在功能上参与并为肿瘤发展所需;通过2）使用LysM Cre-小鼠确定OGR 1在PCa发展中髓系中的作用;以及3）测试OGR 1对肿瘤发生和DP+细胞的作用是否限于某些癌细胞。 目标3。阐明OGR 1在T和DP+细胞中作用的分子机制。 1)研究OGR 1调节DP+细胞中磷酸化酶活性的信号转导机制。 2)阐明TRAMP-C2条件培养基和/或TGF-β 1诱导免疫细胞中OGR 1上调的机制。 3)测试OGR 1特异性激动剂/拮抗剂在免疫细胞和体内的作用。 4)在OGR 1中确定其功能的结构要求。 我们的长期目标是开发基于OGR 1的新型癌症免疫疗法。