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: 7073986
• 负责人: Nancy L. Weigel
• 金额: $ 30.13万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073986
• 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）的激活对降低前列腺癌的风险是有益的，并且VDR激动剂是治疗前列腺癌的潜在治疗剂。 尽管有许多研究表明，VDR激动剂抑制了前列腺癌细胞的生长，但产生这种反应的VDR靶标在大多数情况下是未知的。 在癌细胞系中观察到的变化也将在前列腺肿瘤中发生。此外，除了证明正常主要前列腺上皮细胞的生长也受到VDR激动剂（）的抑制作用，关于VDR在正常前列腺中的作用鲜为人知。对正常和恶性前列腺细胞中VDR作用的更好理解对于评估VDR激动剂为潜在的化学预防和化学治疗剂至关重要。因此，我们建议确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：特定目标1：确定在LNCAP和LAPC-4前列腺癌细胞中受VDR激动剂调控的基因，并确定这些基因是否也受到肿瘤中的调节。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。特定目的3：使用新型的前列腺盘器官培养模型（PDOC）来确定在人体组织中是否概括了细胞培养中发现的变化。将发现从细胞培养和动物模型转化为人类研究的主要局限性之一是临床试验的复杂性和费用。我们提出了一种新的方法，以测试人类前列腺肿瘤的反应以及正常的前列腺组织对VDR激动剂的反应，如果成功的话，不仅会提供有关VDR激动剂效用的信息，而且还将建立一个新的范式来测试小分子对人类肿瘤在临床试验进行临床试验之前对人类肿瘤的影响。特定目的4：评估目标1-3中鉴定的候选受管制基因对对VDR激动剂的反应的贡献。这些目标的成功完成不仅会导致了解VDR激动剂如何有助于减少前列腺发病率和治疗，还可以使我们能够开发方法来预测哪些患者对治疗的反应。