Signaling and Progression in Prostate Cancer

描述(由申请人提供)：前列腺癌患者进展到雄激素非依赖性的中位生存期约为两年。我们计划的目标是阐明信号转导的变化和相关的基因表达变化，这些变化是前列腺癌向雄激素非依赖性状态发展的基础。我们的项目汇集了弗吉尼亚大学和科罗拉多大学富有成效和经验的研究人员，他们拥有实现所述目标所需的互补专业知识。我们的团队包括人类前列腺癌生物学的基础和临床方面的专家(D.Theodresu，科罗拉多州)，信号转导和雄激素受体(B.Paschal，弗吉尼亚州)，以及microRNA调控(A.duta，弗吉尼亚州)。项目1将确定低氧信号是如何被翻译后机制感知并转化为促进前列腺癌进展的基因表达变化的，包括转移。项目2将使用新的小鼠模型来确定PI-3激酶下游的激酶如何协同驱动前列腺癌的发生。项目3将确定microRNA图谱的变化如何调节细胞增殖和前列腺癌向雄激素非依赖性发展。这三个项目得到了三个核心的支持，这三个核心在为方案成员提供支持方面有着良好的记录。CORE A(行政主管，B.Paschal)将通过促进弗吉尼亚州和科罗拉多州站点之间的沟通，并通过满足该计划的生物统计需求(生物统计学家M.Conaway)来提高生产率。CORE B(转基因模型和动物成像；主任，David Wotton)由一位小鼠遗传学专家指导，他将开发用于前列腺癌发生的基因工程小鼠模型，并协助异种移植的生产。CORE C(组织分析总监，H.Frierson)将对小鼠和人类的前列腺进行组织学和免疫组织化学分析。我们的基础和临床科学家团队在定义前列腺癌进展机制方面有着良好的合作记录和共同的愿景。长期目标是将我们对前列腺癌进展机制的理解转化为确定新的药物靶点和临床前模型，概括人类疾病的关键方面。

DESCRIPTION (provided by applicant): The median survival time of men with prostate cancer that progresses to androgen independence is approximately two years. The goal of our Program is to elucidate the alterations in signal transduction and associated changes in gene expression that underlie prostate progression to the androgen independent state. Our Program brings together productive and experienced investigators at the University of Virginia and the University of Colorado with the complementary expertise needed to fulfill the stated goals. Our team includes experts in basic and clinical aspects of human prostate cancer biology (D. Theodorescu; Colorado), signal transduction and the androgen receptor (B. Paschal; Virginia), and microRNA regulation (A. Dutta; Virginia). Project 1 will determine how hypoxic signals are sensed by post-translational mechanisms and transduced into changes in gene expression that promote prostate cancer progression, including metastasis. Project 2 will use new mouse models to determine how kinases downstream of PI-3 kinase cooperate to drive prostate tumorigenesis. Project 3 will determine how changes in microRNA profiles regulate cell proliferation and prostate cancer progression to androgen independence. The three Projects are supported by three Cores that have a strong track record of providing support for Program members. Core A (Administration; Director, B. Paschal) will enhance productivity by facilitating communication between the Virginia and Colorado sites, and by fulfilling biostatistical needs (Biostatistician, M. Conaway) of the Program. Core B (Transgenic Models and Animal Imaging; Director, David Wotton) is directed by a mouse genetics expert who will develop genetically engineered murine models for prostate tumorigenesis, and assist with xenograft production. Core C (Tissue Analysis; Director, H. Frierson) will perform histological and immunohistochemical analysis of mouse and human prostate. Our team of basic and clinician scientists has a track record of collaboration and a shared vision of defining prostate cancer progression mechanisms. The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease.