VITAMIN D RECEPTOR AND REGULATION OF HORMONE RESPONSE

描述：(改编自调查人员摘要)本申请 建议研究维生素D受体(VDR)并检测其 活性形式1，25-二羟基维生素D3(1，25D)的作用 建议的重点是对维生素D和维生素D的研究 调节幅度和性质的各种其他细胞因素 靶组织对1，25D的反应。1，25D响应速度可能是 通过各种细胞机制增加或减少，从而产生 靶细胞的活性光谱从高度敏感到完全 抵抗力强。调查将涉及三个具体目标 影响1，25D反应性调控的因素。 具体目的一、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1，25D抗性综合征家系， 遗传性维生素D抵抗软骨病(HVDRR)及其本质的阐明 VDR基因的突变。此外，它还将确定 靶基因的1，25D非依赖性激活是否是其机制 一些HVDRR儿童通过这种方式“长大”而不再罹患疾病。特定目标II 将研究与VDR(VDR-)相互作用的蛋白质的作用 相互作用的蛋白质或水滴)在介导1，25D的作用中。三个领域 其中将研究的水滴包括：1)寻找新的和未知的 采用GAL4双混合系统的水滴系统；2)调查 相互作用各方面的突变和功能分析 VDR与维甲酸X受体(RXR)的关系，已知与之有关 异源二聚体反式激活靶基因；3)作用的探讨 一种新近被证明能抑制其他蛋白作用的蛋白质 类固醇受体和VDR的受体(如申请人的 初步数据)。特定目标III将研究生理学 维甲酸调节VDR丰度和功能的机制， 糖皮质激素和雌激素。我们将特别注意 前列腺癌和前列腺癌细胞。有很多健康因素-- 该项目的相关方面包括：为目标一，说明 HVDRR家族的突变并提供遗传咨询 描述了一些患有HVDRR的儿童 “长出”他们的遗传缺陷，治愈他们的软骨病；对于AIM II， 调查影响1，25反应的多个因素 正常细胞，并可能处于各种疾病状态；对于AIM III， 1，25与维甲酸、雌激素和维生素A的相互作用 糖皮质激素，所有这些都被用来治疗前列腺癌， 确定1，25D有益效果的增强是否 可以在前列腺癌的治疗中实现。总体而言，赠款 Require是对VDR在1，25D行动中的作用的多方面分析 在不同的健康和疾病状态下，强调 激素反应的遗传和生理调节。

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.