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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

基本信息

批准号：
8843380
负责人：
YAN XU
金额：
$ 40.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/8843380
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 Cre-LoxP 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

项目摘要

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（申请人提供）：我们之前从癌细胞中克隆了一种名为 OGR1 的 G 蛋白偶联受体，并产生了 OGR1 敲除小鼠（ogr1-/-）。我们大量的初步数据表明，OGR1 在免疫细胞中发挥着至关重要的作用，特别是在 T 细胞以及 Gr1 和 CD11b 双阳性 (DP+) 细胞中。我们假设 OGR1 表达不仅影响 DP+ 细胞的数量，还影响前列腺癌 (PCa) 肿瘤细胞攻击后它们的功能； DP+细胞是PCa中OGR1依赖性作用的主要抑制细胞，T细胞是主要效应细胞。这些概念将在三个具体目标中进行测试。该提案的主要目标是确定 OGR1 在免疫细胞中功能的细胞和分子机制，与其在 PCa 肿瘤发生和转移中的作用相关。目的 1. 通过T细胞耗竭和过继转移小鼠体内确定OGR1在T细胞中的功能，研究OGR1在T细胞中在PCa肿瘤发生和转移中的作用； 2) 使用特定的 Cre-Lox 系统在小鼠中检查 OGR1 耗竭对特定 T 细胞谱系的影响； 3)确定ogr1-/-小鼠中T细胞浸润和肿瘤细胞根除的时间过程。目标 2. 通过以下方法确定 OGR1 在 Gr1 和 CD11b 双阳性 (DP+) 细胞中在 PCa 肿瘤发生和转移中的作用： 1) 确定 OGR1 表达，其中免疫细胞群在功能上参与肿瘤发展并为肿瘤发展所必需； 2) 使用 LysM Cre-mice 确定 OGR1 在 PCa 发育中骨髓谱系中的作用； 3) 测试OGR1对肿瘤发生的影响以及DP+细胞是否仅限于某些癌细胞。目标 3. 描述 OGR1 在 T 和 DP+ 细胞中作用的分子机制。 1) 研究OGR1调节DP+细胞中精氨酸酶活性的信号传导机制。 2) 阐明TRAMP-C2条件培养基和/或TGF-β1诱导免疫细胞中OGR1上调的机制。 3）测试OGR1特异性激动剂/拮抗剂在免疫细胞和体内的作用。 4) 确定OGR1中对其功能的结构要求。我们的长期目标是开发基于 OGR1 的新型癌症免疫疗法。