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.

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。这种活性是通过对肠道、肾脏和骨骼的直接作用以及甲状旁腺的反馈调节来实现的。 1,25(OH)2D3 还对多种组织类型发挥额外的生物学作用，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)2D3或其合成衍生物可用于治疗癌症、自身免疫病和皮肤病等适应症。然而，该用途受到1,25(OH)2D3过度诱导肠钙吸收、肾钙重吸收和骨钙重吸收的倾向的困扰。然而，最近，我们对这些生物过程的了解大大增加，这主要是由于关键靶基因的发现，其产物在协调稳态事件中发挥着核心作用。因此，提出了三个具体目标。目标 1：确定 1,25(OH)2D3 基因调节的分子机制，这些基因对于体内肠、肾和骨的钙稳态作用至关重要。我们将使用新颖的分子技术来表征 1,25(OH)2D3 在体内小鼠模型中促进 VDR/RXR DNA 结合、共激活剂相互作用、染色质修饰、RNA pol II 募集以及诱导肾 TRPV5、肠 TRPV6 和骨骼 RankL 基因活性的能力。目标 2：评估细胞内维生素 D 灭活代谢对三个主要器官中 1,25(OH)2D3 活性的作用。我们计划使用 Cyp24a1 null 小鼠探索 Cyp24a1 失活对 1,25(OH)2D3 触发 TRPV5、TRPV6 和 RankL 激活的能力的影响。目标 3：评估经典维生素 D 类似物在体内表现出的生物效力增加和/或选择性改变的潜在机制。我们计划在体内表征三种公认的维生素 D 类似物增强效力、功效和选择性的机制。本文提出的研究将为 1,25(OH)2D3 体内钙活性的潜在机制提供新的见解，定义配体药效学对这些活性的影响，并确定维生素 D 类似物发挥独特的生物效力、功效和选择性的机制。这些概念将为治疗相关维生素 D 类似物的设计和合成提供更合理的方法。公共卫生相关性。维生素 D 在维持矿物质稳态以及控制细胞生长和功能方面发挥着重要作用。本文的研究旨在增强我们对维生素 D 作用机制的理解，以便能够创造出更好、更具选择性的药物。