Targets of Vitamin D Receptor Action in Prostate

前列腺中维生素 D 受体的作用靶点

• 批准号: 6899352
• 负责人: Nancy L. Weigel
• 金额: $ 30.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-02 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899352
• 关键词: angiogenesis; cell growth regulation; chemoprevention; connective tissue cells; epithelium; human subject; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic cell; organ culture; posttranslational modifications; prostate; prostate neoplasms; protein structure function; stimulant /agonist; tissue /cell culture; vitamin D receptors

DESCRIPTION (provided by applicant) There is evidence both that activation of the vitamin D receptor (VDR) is beneficial in reducing the risk of prostate cancer and that VDR agonists are potential therapeutic agents in the treatment of prostate cancer. Although there are numerous studies showing that VDR agonists inhibit prostate cancer cell growth, the VDR targets that produce this response are, for the most part, unknown. Whether the changes observed in cancer cell lines will also occur in prostate tumors has not been addressed. Moreover, other than a demonstration that the growth of normal primary prostatic epithelial cells is also inhibited by VDR agonists (), little is known regarding the role of VDR in normal prostate. A better understanding of VDR action in normal and malignant prostate cells is critical to evaluating VDR agonists as potential chemopreventive and chemotherapeutic agents. Thus, we propose to identify the changes induced by activation of VDR in normal prostate and in tumor cells and to determine which of the changes are critical for the growth regulatory actions. To accomplish these goals, we will: Specific Aim 1: To identify genes regulated by VDR agonists in both LNCaP and LAPC-4 prostate cancer cells and to determine whether these genes are also regulated in tumors. Specific Aim 2: To elucidate the actions of VDR agonists in normal prostate epithelial and stromal cells. Specific Aim 3: Using a novel prostate disc organ culture model (PDOC), to determine whether the changes identified in cell culture are recapitulated in human tissues. One of the major limitations in translating findings from cell culture and animal models to human studies is the complexity and expense of a clinical trial. We propose a novel method to test the response of human prostate tumors as well as normal prostate tissue to VDR agonists that, if successful, will not only provide information regarding the utility of VDR agonists, but will establish a new paradigm for testing the effects of small molecules on human tumors prior to embarking on a clinical trial. Specific Aim 4: To assess the contribution of candidate regulated genes identified in aims 1-3, to the response to VDR agonist. Successful completion of these aims will not only lead to an understanding of how VDR agonists can contribute to reducing prostate incidence and aid in treatment, but may also allow us to develop methods to predict which patients will respond to treatment.

描述（由申请人提供） 有证据表明，维生素 D 受体 (VDR) 的激活有益于降低前列腺癌的风险，而且 VDR 激动剂是治疗前列腺癌的潜在治疗剂。 尽管有大量研究表明 VDR 激动剂可抑制前列腺癌细胞生长，但产生这种反应的 VDR 靶点在很大程度上仍是未知的。 在癌细胞系中观察到的变化是否也会在前列腺肿瘤中发生尚未得到解决。此外，除了证明正常原代前列腺上皮细胞的生长也被VDR激动剂抑制之外，关于VDR在正常前列腺中的作用知之甚少。更好地了解 VDR 在正常和恶性前列腺细胞中的作用对于评估 VDR 激动剂作为潜在的化学预防和化疗药物至关重要。因此，我们建议鉴定正常前列腺和肿瘤细胞中 VDR 激活引起的变化，并确定哪些变化对于生长调节作用至关重要。为了实现这些目标，我们将： 具体目标 1：鉴定 LNCaP 和 LAPC-4 前列腺癌细胞中受 VDR 激动剂调节的基因，并确定这些基因是否也在肿瘤中受到调节。具体目标 2：阐明 VDR 激动剂在正常前列腺上皮细胞和基质细胞中的作用。具体目标 3：使用新型前列腺盘器官培养模型 (PDOC)，以确定细胞培养中发现的变化是否在人体组织中重现。将细胞培养和动物模型的研究结果转化为人类研究的主要限制之一是临床试验的复杂性和费用。我们提出了一种新方法来测试人类前列腺肿瘤以及正常前列腺组织对 VDR 激动剂的反应，如果成功，不仅将提供有关 VDR 激动剂效用的信息，而且将建立一个新的范例来测试 VDR 激动剂的效果在开始临床试验之前对人类肿瘤进行小分子研究。具体目标 4：评估目标 1-3 中确定的候选调控基因对 VDR 激动剂反应的贡献。成功完成这些目标不仅将有助于了解 VDR 激动剂如何有助于降低前列腺发病率并帮助治疗，而且还可能使我们能够开发出预测哪些患者将对治疗产生反应的方法。