PROSTATE CANCER, CALCIUM AND VITAMIN D

描述（由申请人提供）： 尽管有流行病学证据表明饮食中的钙和维生素D与前列腺癌风险有关，但基础和临床前研究的有限性排除了为有前列腺癌风险的男性或患有前列腺癌的男性制定关于摄入这些营养素的具体建议。患有前列腺癌的男性可能会自我治疗或寻求补充和替代药物，包括钙或维生素D补充剂，但这种治疗对疾病进展或治疗反应的影响尚不清楚。在拟议的研究中，我们将使用转基因，基因敲除和异种移植动物模型来测试的假设是，维生素D受体代表营养调制的前列腺生长调节基因。1，25 D是维生素D衍生的VDR的配体，在正常和转化的前列腺细胞中诱导生长停滞、分化和凋亡。由于膳食钙是循环1，25 D的主要决定因素，因此该假设的推论是钙消耗将通过调节维生素D内分泌系统间接影响前列腺癌。三个具体目标已被设计来测试这一假设：目标1。确定膳食钙或VDR信号的改变是否可以预防转基因小鼠模型中的前列腺肿瘤发生。目标2.评估膳食钙和维生素D类似物对早期人类前列腺癌进展的影响。目标3.确定前列腺肿瘤发生中钙和VDR调节的细胞靶点。在目标1和目标2中，我们将全面评估膳食钙和维生素D状况对前列腺肿瘤发生、进展和转移以及对抗雄激素治疗的反应的影响。目标3中的实验将鉴定基因靶标，并提供氧化还原信号传导在调节膳食钙和维生素D对正常前列腺生物学、肿瘤起始、局部和转移进展的影响中的作用的机制理解。这些研究对RFA #CA-03-003，前列腺癌预防营养素的分子靶点高度响应，并有可能影响前列腺癌风险男性或患有前列腺癌的男性的饮食建议。

DESCRIPTION (provided by applicant): Despite epidemiological evidence linking dietary calcium and vitamin D to prostate cancer risk, the limited availability of basic and pre-clinical research precludes the development of specific recommendations regarding intake of these nutrients for men at risk of prostate cancer or those living with the disease. Men with prostate cancer may self medicate or seek complementary and alternative medicines, including calcium or vitamin D supplements, however the impact of such practises on disease progression or response to therapy is unknown. In the proposed studies, we will use transgenic, knockout and xenograft animal models to test the hypothesis is that the vitamin D receptor represents a nutritionally modulated growth regulatory gene in prostate. 1,25D, the ligand for the VDR which is derived from vitamin D, induces growth arrest, differentiation and apoptosis in normal and transformed prostate cells. Since dietary calcium is the major determinant of circulating 1,25D, a corollary to this hypothesis is that calcium consumption will indirectly affect prostate cancer via modulation of the vitamin D endocrine system. Three specific aims have been designed to test this hypothesis: Aim 1. To determine whether alterations in dietary calcium or VDR signaling can prevent prostate tumorigenesis in a transgenic mouse model. Aim 2. To assess the impact of dietary calcium and a vitamin D analog on progression of early stage human prostate cancer. Aim 3. To identify cellular targets for calcium and VDR modulation of prostate tumorigenesis. In Aim 1 and 2, we will comprehensively evaluate the effects of dietary calcium and vitamin D status on prostate tumor initiation, progression and metastasis and response to anti-androgen therapy. The experiments in Aim 3 will identity gene targets and provide mechanistic understanding of the role of redox signaling in modulating the effects of dietary calcium and vitamin D on normal prostate biology, tumor initiation, local and metastatic progression. These studies are highly responsive to RFA #CA-03-003, Molecular Targets for Nutrients in Prostate Cancer Prevention, and have the potential to impact on dietary recommendations for men at risk for prostate cancer or those living with the disease.