Vitamin D Ligands and Regulation of Calcium Homeostasis

维生素 D 配体和钙稳态调节

• 批准号: 7461164
• 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/7461164
• 关键词: Appearance; Autoimmune Process; Biological; Calcitriol; Calcium; Chromatin; DNA Binding; DNA Polymerase II; Event; Feedback; Gene Targeting; Genes; Histocompatibility Testing; Homeostasis; Intestines; Kidney; Knockout Mice; Ligands; Maintenance; Malignant Neoplasms; Medicine; Metabolism; Minerals; Modeling; Modification; Molecular; Organ; Organism; Parathyroid gland; Pharmacodynamics; Physiological; Plague; Play; Process; Public Health; RNA; Range; Regulation; Research; Role; Side; Skeletal system; Techniques; Tissues; Vitamin D; Vitamin D Analog; absorption; bone; cell growth; concept; design; in vivo; insight; mouse model; novel; skin disorder

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. PUBLIC HEALTH RELEVANCE. Vitamin D plays significant roles both in the maintenance of mineral homeostasis and in the control of cellular growth and function. The studies herein seek to enhance our understanding of the mechanisms that underlie vitamin D action such that better and more selective medicines can be created.

说明（由申请人提供）：1，25-二羟基维生素D3（1，25（OH）2D 3）的经典功能是维持脊椎动物体内的钙稳态。这种活性是通过对肠、肾和骨的直接作用和在甲状旁腺的反馈调节来实现的。1，25（OH）2D 3还对广泛的组织类型发挥额外的生物作用，主要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）2D 3或其合成衍生物可以在治疗上用于诸如癌症、自身免疫性疾病和皮肤病的适应症。然而，这种效用受到1，25（OH）2D 3过度诱导肠钙吸收、肾钙重吸收和骨钙再吸收的倾向的困扰。然而，最近，我们对这些生物过程的理解大大增加，这主要是由于发现了关键靶基因，其产物在协调稳态事件中起着核心作用。因此，提出了三个具体目标。目标1：确定1，25（OH）2D 3对体内肠、肾和骨钙稳态作用的核心基因调控的分子机制。我们将使用新的分子技术来表征1，25（OH）2D 3在体内小鼠模型中促进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TRPV 5、肠TRPV 6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）2D 3活性的作用。我们计划使用Cyp 24 a1敲除小鼠探索Cyp 24 a1失活对1，25（OH）2D 3触发TRPV 5、TRPV 6和RankL激活能力的影响。目标三：评估经典维生素D类似物在体内表现出的生物效价增加和/或选择性改变的潜在机制。我们计划在体内的机制，负责提高效力，疗效和选择性的三个公认的维生素D类似物的特点。本文提出的研究将提供新的见解的潜在机制负责钙离子活性的1，25（OH）2D 3在体内，定义的影响配体药效学对这些活动，并确定机制，使维生素D类似物发挥独特的混合物的生物效力，疗效和选择性。这些概念将使更多的合理的方法来设计和合成治疗相关的维生素D类似物。公共卫生相关性。维生素D在维持矿物质稳态和控制细胞生长和功能方面都起着重要作用。本文的研究旨在提高我们对维生素D作用机制的理解，以便创造出更好、更具选择性的药物。