Vitamin D Ligands and Regulation of Calcium Homeostasis

维生素 D 配体和钙稳态调节

• 批准号: 7591143
• 负责人: J WESLEY PIKE
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591143
• 关键词: Appearance; Autoimmune Process; Biological; Biological Assay; Blood; Bone Resorption; Calcitriol; Calcium; Calcium Channel; Cell model; Cells; Cessation of life; Chromatin Structure; Clinical; DNA Binding; DNA Polymerase II; Disease; Enzymes; Event; Exhibits; Failure; Feedback; Gatekeeping; Gene Expression; Gene Targeting; Genes; Goals; Half-Life; Histocompatibility Testing; Homeostasis; Hormones; Hypercalcemia; Immune system; Intestines; Kidney; Kinetics; Knockout Mice; Lead; Ligands; Location; Maintenance; Malignant Neoplasms; Mediating; Medicine; Metabolism; Minerals; Molecular; Mus; Nucleic Acid Regulatory Sequences; Organ; Organism; Parathyroid gland; Pharmacodynamics; Phosphorus; Physiological; Plague; Play; Process; Production; Property; Psoriasis; RNA; Regulation; Research; Role; Side; Signal Transduction; Techniques; Therapeutic; Tissues; Vitamin D; Vitamin D Analog; Vitamins; analog; animal model development; base; bone; calcium absorption; cell growth; chromatin modification; design; hormone analog; hypercalciuria; in vivo; in vivo Model; insight; mouse model; novel; prevent; release of sequestered calcium ion into cytoplasm; response; reuptake; skeletal; skin disorder; steroid hormone; uptake

DESCRIPTION (provided by applicant): A classical function of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is to maintain calcium homeostasis in vertebrate organisms. This activity is achieved through direct actions on intestine, kidney and bone, and feedback regulated at the parathyroid gland. 1,25(OH)2D3 also exerts additional biologic actions on a wide range of tissue types, primarily as a regulator of cell growth and differentiation. These highly pleiotropic actions suggest that 1,25(OH)2D3 or synthetic derivatives thereof may be useful therapeutically for such indications as cancer, and autoimmune and skin diseases. This utility is plagued, however, by the propensity for 1,25(OH)2D3 to hyper-induce intestinal calcium absorption, renal calcium reabsorption and bone calcium resorption. Recently, however, our understanding of these biologic processes has increased substantially, due largely to the discovery of key target genes whose products play central roles in orchestrating the homeostatic events. As a consequence, three specific aims are proposed. Aim 1: To determine the molecular mechanisms that underlie the regulation by 1,25(OH)2D3 of genes that are central to the calcium homeostatic actions of intestine, kidney and bone in vivo. We will use novel molecular techniques to characterize 1,25(OH)2D3`s ability to promote VDR/RXR DNA binding, coactivator interaction, chromatin modification, RNA pol II recruitment, and induction of renal TRPV5, intestinal TRPV6, and skeletal RankL gene activity in a mouse model in vivo. Aim 2: To evaluate the role of intracellular, vitamin D-inactivating metabolism on 1,25(OH)2D3 activity in the three primary organs. We plan to explore the consequence of Cyp24a1 inactivation on 1,25(OH)2D3`s ability to trigger TRPV5, TRPV6 and RankL activation using the Cyp24a1 null mouse. Aim 3: To assess the underlying mechanisms responsible for the increased biological potency and/or altered selectivity manifested by classic vitamin D analogues in vivo. We plan to characterize in vivo the mechanisms responsible for the increased potency, efficacy and selectivity for three well recognized vitamin D analogues. The research proposed herein will provide novel insight into the underlying mechanisms responsible for the calcemic activity of 1,25(OH)2D3 in vivo, define the impact of ligand pharmacodynamics on these activities and identify mechanisms whereby vitamin D analogues exert unique blends of biologic potency, efficacy and selectivity. These concepts will enable more rationale approaches to the design and synthesis of therapeutically relevant vitamin D analogues.

描述（由申请人提供）：1,25-二羟基维生素D3 （1,25(OH)2D3）的经典功能是维持脊椎动物体内的钙稳态。这种活性是通过直接作用于肠道、肾脏和骨骼，并在甲状旁腺进行反馈调节来实现的。1,25(OH)2D3还对多种组织类型发挥额外的生物作用，主要是作为细胞生长和分化的调节剂。这些高度多效性的作用表明，1,25(OH)2D3或其合成衍生物可用于治疗癌症、自身免疫性疾病和皮肤病等适应症。然而，125 (OH)2D3倾向于过度诱导肠道钙吸收、肾脏钙再吸收和骨钙吸收，这一效用受到了困扰。然而，最近，我们对这些生物过程的理解有了很大的提高，这主要是由于发现了关键的靶基因，其产物在协调体内平衡事件中起着核心作用。因此，提出了三个具体目标。目的1：确定1225 (OH)2D3调控基因的分子机制，这些基因是体内肠道、肾脏和骨骼钙稳态作用的核心。我们将使用新的分子技术来表征1,25(OH)2D3在小鼠体内模型中促进VDR/RXR DNA结合、共激活因子相互作用、染色质修饰、RNA pol II募集以及诱导肾脏TRPV5、肠道TRPV6和骨骼RankL基因活性的能力。目的2：评估细胞内维生素d失活代谢对三个主要器官中1,25(OH)2D3活性的作用。我们计划利用Cyp24a1缺失小鼠来探索Cyp24a1失活对1,25(OH)2D3触发TRPV5、TRPV6和RankL激活能力的影响。目的3：评估体内经典维生素D类似物增加生物效力和/或改变选择性的潜在机制。我们计划在体内描述三种公认的维生素D类似物的效力、功效和选择性增加的机制。本文提出的研究将为体内1,25(OH)2D3钙化活性的潜在机制提供新的见解，确定配体药效学对这些活性的影响，并确定维生素D类似物发挥独特生物效力，功效和选择性的机制。这些概念将为设计和合成治疗相关的维生素D类似物提供更合理的方法。