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：
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
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/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

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（由申请人提供）：我们先前以癌细胞和产生的OGR1基因敲除小鼠（OGR1 - / - ）称为OGR1的G蛋白偶联受体（OGR1-/ - ）。我们的大量初步数据表明，OGR1在免疫细胞以及T细胞以及GR1和CD11b双重阳性（DP+）细胞中起着至关重要的作用。我们假设OGR1表达不仅会影响DP+细胞的数量，还会影响前列腺癌（PCA）肿瘤细胞挑战后其功能。 DP+细胞是主要的抑制细胞，T细胞是PCA中OGR1-抑制效应的主要效应细胞。这些概念将以三个特定目标进行测试。该建议的主要目的是确定与PCA肿瘤发生和转移相关的免疫细胞功能中OGR1功能的细胞和分子机制。 AIM 1。通过1）使用T细胞耗尽和收养转移小鼠来确定OGR1在PCa肿瘤发生和转移中T细胞中T细胞中T细胞的作用；通过2）使用小鼠中特定的CRE-LOX系统检查OGR1耗竭在特定T细胞谱系中的影响； 3）确定OGR1 - / - 小鼠中T细胞浸润和消除肿瘤细胞的时间过程。 AIM 2。通过1）确定OGR1在PCA肿瘤发生和转移中确定OGR1在GR1和CD11b双重阳性（DP+）中的作用1）确定OGR1表达在功能上涉及免疫细胞群体，并且需要肿瘤发育；通过2）确定使用LYSM CRE鼠标在PCA发育中确定OGR1在PCA发育中的作用； 3）测试OGR1对肿瘤发生和DP+细胞的影响是否仅限于某些癌细胞。 AIM 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+细胞精氨酸活性的信号传导机制。 2）阐明了流浪性-C2条件培养基和/或TGF-BETA1在免疫细胞中诱导OGR1上调的机制。 3）测试免疫细胞和体内OGR1特异性激动剂/拮抗剂的影响。 4）确定OGR1中其功能的结构要求。我们的长期目标是为癌症开发基于OGR1的新型免疫疗法。