Signaling and Progression in Prostate Cancer

描述（由申请人提供）：进展为雄激素非依赖性的前列腺癌男性的中位生存时间约为两年。我们项目的目标是阐明前列腺进展为雄激素非依赖性状态的信号转导和相关基因表达变化的改变。我们的计划汇集了弗吉尼亚大学和科罗拉多大学富有成效和经验丰富的调查人员，他们具有实现既定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基础和临床方面的专家（D。Theodorescu;科罗拉多）、信号转导和雄激素受体（B. Paschal; Virginia）和microRNA调控（A. Dutta; Virginia）。项目1将确定低氧信号如何被翻译后机制感知，并转化为促进前列腺癌进展（包括转移）的基因表达变化。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合作驱动前列腺肿瘤发生。项目3将确定microRNA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的进展。这三个项目得到三个核心的支持，这些核心在为项目成员提供支持方面有着良好的记录。核心A（行政;主任，B。Paschal）将通过促进弗吉尼亚和科罗拉多研究中心之间的沟通以及满足生物统计学需求来提高生产率（生物统计学家，M。Conaway）的方案。核心B（转基因模型和动物成像;主任，大卫沃顿）由小鼠遗传学专家指导，他将开发用于前列腺肿瘤发生的基因工程小鼠模型，并协助异种移植物的生产。核心C（组织分析;主管，H. Frierson）将对小鼠和人类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有着合作的记录，并对定义前列腺癌进展机制有着共同的愿景。长期目标是将我们对前列腺癌进展机制的理解转化为新的药物靶点和临床前模型的鉴定，这些模型概括了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.