Project 1 Pilot Research Project

试点项目：摘要 前列腺癌（CaP）仍然是美国和世界范围内的主要健康问题。可用临床和 实验室结果证明雄激素受体（AR）在开始和进展中起关键作用， 去势抵抗性疾病然而，尽管经过几十年的巨大努力， 通过靶向AR治疗晚期CaP仍然难以捉摸，这意味着存在逃逸 通过其他促成因素的作用。我们的实验室和其他人的工作 在过去的几十年中，已经证明了G蛋白偶联受体（GPCR）信号传导和调节这种作用。 GPCR激酶（GRKs）及其底物在前列腺癌发生中的信号传导。我们最近的观察 证明GRK 5，一种普遍存在的S/T激酶，在人CaP细胞中表达并调节前列腺 肿瘤生长和转移。GRK 5活性的抑制阻断CaP细胞周期进展和增殖。 此外，GRK 5活性的抑制减弱了CaP细胞的迁移和侵袭，并且一致地， 增加细胞附着和粘着斑形成。CaP磷酸化蛋白质组的质谱分析 揭示了ERM蛋白膜突蛋白作为一种新的（和非GPCR）GRK 5底物，介导细胞迁移 和入侵。该项目的科学目标是确定膜突蛋白在GRK 5调节的前列腺中的作用。 肿瘤生长和转移（目的1）。这项研究的指导假设是， GRK 5的表达/活性通过调节前列腺肿瘤的生长和转移而参与前列腺肿瘤的生长和转移。 膜突蛋白活性这项研究计划的培训目标是提供早期职业少数民族癌症研究人员 (Dr. Selina Darling-Reed），在前列腺癌细胞生物学（Aim 2）方面有很强的背景。通过收购 板凳技能，在科学理论和专业发展的指导，该计划旨在提供 培训生拥有一套全面的工具，在癌症研究领域取得成功。超出 Darling-Reed博士将受益于出色的环境和一群同事 在UF。预计这些经验将为她提供必要的各方面准备， 培养对前列腺癌研究浓厚兴趣，以获得独立和成功的学术生涯。

PILOT PROJECT: ABSTRACT Prostate cancer (CaP) continues to be a major health problem in the US and worldwide. Available clinical and laboratory outcomes evidence a critical role for androgen receptor (AR) in both the initiation and progression to castration-resistant disease. However, despite monumental efforts spanning many decades, successful treatment of advanced CaP through the targeting of AR remains elusive, implying existence of escape mechanisms through the action of additional contributing factors. Work from our laboratory and others over the past decades has demonstrated a role for G protein-coupled receptor (GPCR) signaling and regulation of this signaling by GPCR kinases (GRKs) and their substrates in prostate carcinogenesis. Our recent observations demonstrate that GRK5, a ubiquitous S/T kinase, is expressed in human CaP cells and regulates prostate tumor growth and metastasis. Inhibition of GRK5 activity blocks CaP cell cycle progression and proliferation. Moreover, the inhibition of GRK5 activity attenuates CaP cell migration and invasion and, concordantly, increases cell attachment and focal adhesion formation. Mass spectrometry of the CaP phosphoproteome revealed the ERM protein moesin as a novel (and non-GPCR) GRK5 substrate that mediates the cell migration and invasion. The scientific goal of this program is to establish role of moesin in the GRK5-regulated prostate tumor growth and metastasis (Aim 1). The guiding hypothesis for this study is that unregulated expression/activity of GRK5 is involved in prostate tumor growth and metastasis through the regulation of moesin activity. The training goal of this research program is to provide early career minority cancer researcher (Dr. Selina Darling-Reed) with strong background in prostate cancer cell biology (Aim 2). Via the acquisition of bench skills, instruction in scientific theory and professional development, this program seeks to provide the trainee with a comprehensive set of tools necessary to launch a successful career in cancer research. Beyond the laboratory training, Dr. Darling-Reed will benefit from an outstanding environment and group of colleagues at the UF. It is anticipated that these experiences will provide her with all aspects of preparation necessary to hone a keen interest in prostate cancer research for an independent and successful academic career.