VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

描述：（改编自研究者摘要）本申请 建议研究维生素D受体（VDR），并检查其 在活性形式1，25-二羟维生素D3（1，25 D）的作用中的作用 维生素D 该提案的重点是对VDR的研究， 各种其他细胞因子， 靶组织对1, 25 D的反应 1、25 D响应性可能是 通过各种细胞机制增加或减少，产生 靶细胞中从高度敏感到完全敏感的活性谱 抵抗 在调查中要解决三个具体目标 的因素，有助于1，25 D反应的调节。 具体目的：探讨靶器官的遗传机制 由于VDR突变而产生的耐药性。 它将审查一些新的 靶器官对1，25 D抵抗综合征家系， 遗传性抗维生素D佝偻病（HVDRR），并阐明其性质 VDR基因的突变。 此外，它将确定 靶基因的1，25 D非依赖性激活是否是 一些HVDRR儿童通过这种方式“长大”而不再患病。 具体目标II 将研究与VDR相互作用的蛋白质的作用（VDR- 相互作用蛋白或DRIP）介导1，25 D作用。 三个领域 其中DRIP将研究包括：1）寻找新的和未知的 采用GAL 4双混合系统的DRIP; 2）通过 相互作用的各个方面的突变和功能分析 维生素A X受体（RXR）的VDR，它是已知的， 异源二聚体化以反式激活靶基因; 3）探索作用 钙网蛋白，一种最近被证明可以抑制其他蛋白质的作用的蛋白质， 类固醇受体和VDR的受体（如本申请人的 初步数据）。 具体目标III将研究生理 类维生素A调节VDR丰度和功能的机制， 糖皮质激素和雌激素。 将特别注意 前列腺和前列腺癌细胞。 许多健康- 项目的相关方面，包括：对于目标I，阐明 HVDRR家族中的突变，并提供遗传咨询，以及 描述了一些患有HVDRR的儿童 “长大”后，他们的遗传缺陷和治愈他们的佝偻病;为目标二， 研究调节1，25反应性的多种因素， 正常细胞和潜在的各种疾病状态;以及对于目标III， 探索1，25与类维生素A、雌激素和 糖皮质激素，所有这些都被用来治疗前列腺癌， 为了确定是否增强1，25 D的有益效果， 可以在前列腺癌的治疗中实现。 总的来说， 请求是对VDR在1，25 D行动中的作用的多方面分析 在不同的健康和疾病状态，强调的主题， 激素反应性的遗传和生理调节。

DESCRIPTION: (Adapted from investigator's abstract) This application proposes to investigate the vitamin D receptor (VDR) and to examine its role in the action of 1,25-dihydroxyvitamin D3 (1,25D), the active form of vitamin D. The focus of the proposal is the study of the VDR and various other cellular factors that modulate the amplitude and nature of the target tissue responses to 1,25D. 1,25D responsiveness may be increased or decreased by a variety of cellular mechanisms, yielding a spectrum of activity in target cells from highly sensitive to totally resistant. Three Specific Aims are to be addressed in the investigation of factors that contribute to the regulation of 1,25D responsiveness. Specific Aim I will probe into the genetic mechanisms of target organ resistance due to mutations in the VDR. It will examine a number of new families with the syndrome of target organ resistance to 1,25D, Hereditary Vitamin D Resistant Rickets (HVDRR), and elucidate the nature of the mutations in the VDR gene. In addition, it will determine whether 1,25D- independent activation of target genes is the mechanism by which some HVDRR children "outgrow" their disease. Specific Aim II will investigate the role of proteins that interact with the VDR (VDR- Interacting Proteins or DRIPs) in mediating 1,25D action. Three areas in which DRIPs will be studied include: 1) a search for new and unknown DRIPs employing the GAL4 Two-Hybrid System; 2) investigation by mutational and functional analyses of various aspects of the interaction of VDR with the retinoid X receptor (RXR), with which it is known to heterodimerize to transactivate target genes; 3) exploration of the role of calreticulin, a protein recently shown to inhibit the action of other steroid receptors and that of VDR (as shown by the applicants' preliminary data). Specific Aim III will study the physiological mechanisms by which VDR abundance and function is modulated by retinoids, glucocorticoids and estrogens. Special attention will be addressed to the prostate gland and prostate cancer cells. There are many health- related aspects of the project including: for Aim I, the elucidation of mutations in HVDRR families and providing genetic counseling, as well as delineating the mechanisms by which some children with HVDRR "outgrow" their genetic defect and heal their rickets; for Aim II, investigating multiple factors that modulate 1,25 responsiveness in normal cells and potentially in various disease states; and for Aim III, exploration of the interaction of 1,25 with retinoids, estrogens and glucocorticoids, all of which have been used to treat prostate cancer, to determine whether an enhancement of the beneficial effects of 1,25D can be achieved in the therapy of prostate cancer. Overall, the grant request is a multi-faceted analysis of the role of VDR in 1,25D action in various states of health and disease, emphasizing the themes of genetic and physiological regulation of hormone responsiveness.