Pilot Project #2

项目摘要：前列腺癌(Pca)是最常见的非皮肤恶性肿瘤，其次是癌症 对美国男性的死亡负有责任。先前对前列腺癌动物模型和人类的研究 证明了前列腺会产生各种生长因子。这些因子的加入或阻断改变了PCA细胞 具有增殖等功能。在这些因子中，转化生长因子-β-1(转化生长因子-β)参与了 致瘤性，显示出强大的免疫抑制活性，是转换传统的CD4+所必需的 T细胞转化为FoxP3+调节性T(Tr)细胞。表达转录因子Foxp3的TR细胞对正常 免疫功能；缺乏tr细胞会导致多器官自身免疫和死亡。明确转化生长因子-β的作用及其机制 在前列腺癌的发生和发展过程中对TR值的影响缺乏实验证据。 在这项提案中，我们计划研究转化生长因子-β和/或tr的潜在机制。 来自前列腺癌转基因小鼠(TRAMP)的Pca细胞系，在C57/B6小鼠中。在这些细胞系中， TRAMP-C1和TRAMP-C2形成肿瘤；TRAMP-C3不能形成肿瘤。这些前列腺癌小鼠细胞系可用于 获得这个项目的长期目标，即解决根本问题：是否要做tr细胞和/或转化生长因子-β 水平与TRAMP细胞系(C1、C2和C3)致瘤性的差异有关？这个项目的目标是 确定宿主细胞产生转化生长因子-β对TRAMP细胞系的反应或转化生长因子-β表达的作用 探讨转化生长因子-β在初始CD_4~+T细胞向表达Foxp3的T细胞转化中的作用。

Project Summary: Prostate cancer (PCa) is the most common non-skin malignancy and the cancer second most responsible for death in men in United States. Prior studies with animal models of PCa and with humans demonstrated that the prostate produces various growth factors. Addition or blocking of these factors alters PCa cell proliferation and other functions. Among these factors, transforming growth factor-β1 (TGF-β) is involved in tumorigenicity, displays potent immunosuppressive activities, and is required for the conversion of conventional CD4+ T cells to FoxP3+ regulatory T (TR) cells. TR cells that express the transcription factor Foxp3 are essential for normal immune function; absence of TR cells results in multi-organ autoimmunity and death. A clear role of TGF-β and its effect on TR during PCa development and progression lacks experimental evidence. In this proposal, we plan to investigate the underlying mechanisms involved in the context of TGF-β and/or TR using PCa cell lines, derived from transgenic mouse for prostate cancer (TRAMP), in C57/B6 mice. Of these cell lines, TRAMP- C1 and TRAMP-C2 form tumors; TRAMP-C3 fails to do so. These mouse cell lines of PCa can be used to obtain the long-term goal of this project, which is to address the fundamental question: Do TR cells and/or TGF-β levels relate to differences in tumorigenicity of the TRAMP cell lines (C1, C2, and C3)? The objective of this project is to define the role of TGF-β production by host cells in response to or TGF-β expression by TRAMP cell lines and to establish the function of TGF-β on the conversion of naive CD4+ T cells into Foxp3-expressing TR cells.