Vitamin D Ligands and Regulation of Calcium Homeostasis

维生素 D 配体和钙稳态调节

基本信息

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
项目类别：
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

项目摘要

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生物体中的钙稳态。通过直接对肠道，肾脏和骨骼的作用以及在甲状旁腺调节的反馈来实现此活动。 1,25（OH）2d3还对多种组织类型发挥了其他生物学作用，主要是细胞生长和分化的调节剂。这些高度的多效性作用表明1,25（OH）2d3或其合成衍生物可能在癌症，自身免疫性和皮肤疾病等适应症的治疗上可能是有用的。然而，由于1,25（OH）2d3的倾向，该效用受到了诱导肠道钙吸收，肾钙的吸收和骨钙吸收的倾向。然而，最近，我们对这些生物学过程的理解大大增加了，这主要是由于发现关键靶基因在策划稳态事件中起着重要作用的关键靶基因。结果，提出了三个具体目标。目的1：确定由1,25（OH）2d3的基因的分子机制的基因，这些基因是体内肠，肾脏和骨骼钙稳态作用的核心。我们将使用新颖的分子技术来表征1,25（OH）2D3的能力，能够促进VDR/RXR DNA结合，共激活因子相互作用，染色质修饰，RNA POL II募集以及肾脏TRPV5，肠TRPV6和肠trpv6和骨骼骨骼rankL基因活性在VIVO中的小鼠模型中。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。我们计划在1,25（OH）2d3的能力上探索CYP24A1灭活的后果，使用CYP24A1 NULL鼠标触发TRPV5，TRPV6和RANKL激活。目的3：评估负责生物学效力增加和/或体内经典维生素D类似物所表现出的选择性增加的基本机制。我们计划在体内表征导致三种公认的维生素D类似物的效力，疗效和选择性提高的机制。本文提出的研究将提供对负责1,25（OH）2d3在体内造币活性的潜在机制的新见解，它定义了配体药效学对这些活性的影响，并确定了维生素D模拟物具有独特的生物效率，效率，效率和选择性的独特混合物。这些概念将使更多的基本原理方法来设计和合成治疗相关的维生素D类似物。