1,25-Dihydroxyvitamin D and vitamin D Receptor Function in the Zebrafish Skeleton

斑马鱼骨骼中 1,25-二羟基维生素 D 和维生素 D 受体的功能

• 批准号: 8131697
• 负责人: RAJIV KUMAR
• 金额: $ 17.03万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-18 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131697
• 关键词: 1,25 (OH) vitamin D; Adult; Aging; Animal Model; Bone Morphogenetic Proteins; Brain; Calcium; Cartilage; Cells; Chondrocytes; Data; Dendritic Cells; Ear; Embryo; Endocrine; Epithelial; Epithelial Cells; Eye; Fertilization; Fishes; Growth Factor; Human; Immune system; Intestines; Kidney; Maintenance; Mammals; Methods; Minerals; Morphology; Nutrient; Oligonucleotides; Organ; Organism; Osteoblasts; Osteoporosis; Ovary; Pancreas; Pathway interactions; Role; Signal Transduction; Skeletal Development; Skeleton; Staging; Sterols; T-Lymphocyte; Testis; Tissues; Vitamin D; Vitamin D3 Receptor; Vitamins; Zebrafish; bone; bone health; bone loss; bone morphogenetic protein receptors; calcium phosphate; cartilage development; insight; knock-down; macrophage; prevent; public health relevance; receptor; receptor expression; receptor function; relating to nervous system; skeletal; zebrafish development

DESCRIPTION (provided by applicant): The objective of this application is to elucidate the functions of 1a, 25-dihydroxyvitamin D3 (1a,25(OH)2D3) and its receptor, the 1a,25(OH)2D3 receptor (VDR), in tissues in which it does not have a role in trans-epithelial calcium (Ca) and phosphate (Pi) transport ("non-classical" effects) using the zebrafish, Danio rerio as a model organism. We have recently shown that the VDR is expressed in tissues of the adult and developing zebrafish, Danio rerio. The VDR is present in the developing cartilage, bone, brain, eye, and ear of the zebrafish early after fertilization. The hypothesis is that 1a,25(OH)2D3 and the VDR alter cartilage development and maturation in zebrafish by regulating the expression of bone morphogenetic proteins (BMPs) and BMP receptors. In aim 1 we will examine the effects of 1a,25(OH)2D3 on skeletal development in Danio rerio. We will administer 1a,25(OH)2D3 to developing zebrafish embryos to determine whether 1a,25(OH)2D3 administration alters BMP and BMP receptor expression, BMP signaling and cartilage development and skeletal morphology. In aim 2, we will determine the effects of "knocking down" VDR expression in the developing zebrafish embryo with anti-sense morpholino oligonucleotides methods. The effect of VDR knock- down on zebrafish embryo BMP and BMP receptor expression, BMP signaling and cartilage development and skeletal morphology will be assessed. Significance: The effects of 1a,25(OH)2D3 and its receptor have been extensively examined in mammals and humans with respect to their effects on Ca transport. Effects that are independent of Ca transport have not, however, been examined in detail. By examining the effects of 1a,25(OH)2D3 and the VDR on skeletal development in zebrafish embryos through BMP pathways, we will be able to delineate the direct and Ca-independent effects of 1a,25(OH)2D3 and the VDR in cartilage. We will also establish the zebrafish as a new model organism in which to examine the effects of 1a,25(OH)2D3. PUBLIC HEALTH RELEVANCE: Vitamin D is important for the maintenance of bone health. In this project we will examine how the vitamin and its receptor function in bone and cartilage by studying their effects in a model organism, the developing zebrafish. By examining the effects of active vitamin D and its receptor on growth factors that influence skeletal development we will gain insights into how the vitamin functions in bone. This information will be of use in preventing bone loss that occurs with aging and in treating osteoporosis.

描述（由申请人提供）：本申请的目的是阐明1a，25-二羟基维生素D3（1a，25（OH）2D3）及其受体1a，25（OH）2D3受体（VDR）的功能，使用斑马鱼、丹尼奥在跨上皮钙 (Ca) 和磷酸盐 (Pi) 运输（“非经典”效应）中不发挥作用的组织中斑马鱼作为模式生物。我们最近发现，VDR 在成年斑马鱼和发育中的斑马鱼（斑马鱼）的组织中表达。 VDR 存在于斑马鱼受精后早期发育中的软骨、骨骼、大脑、眼睛和耳朵中。假设 1a,25(OH)2D3 和 VDR 通过调节骨形态发生蛋白 (BMP) 和 BMP 受体的表达来改变斑马鱼的软骨发育和成熟。在目标 1 中，我们将研究 1a,25(OH)2D3 对斑马鱼骨骼发育的影响。我们将对发育中的斑马鱼胚胎施用 1a,25(OH)2D3，以确定 1a,25(OH)2D3 施用是否会改变 BMP 和 BMP 受体表达、BMP 信号传导以及软骨发育和骨骼形态。在目标 2 中，我们将使用反义吗啉代寡核苷酸方法确定发育中斑马鱼胚胎中“敲低”VDR 表达的效果。将评估 VDR 敲低对斑马鱼胚胎 BMP 和 BMP 受体表达、BMP 信号传导以及软骨发育和骨骼形态的影响。意义：1a,25(OH)2D3 及其受体在哺乳动物和人类中对 Ca2+ 转运的影响已得到广泛研究。然而，独立于 Ca2+ 转运的影响尚未得到详细研究。通过 BMP 途径检查 1a,25(OH)2D3 和 VDR 对斑马鱼胚胎骨骼发育的影响，我们将能够描述 1a,25(OH)2D3 和 VDR 在斑马鱼胚胎中的直接和不依赖于 Ca 的影响。软骨。我们还将建立斑马鱼作为新的模式生物来检查 1a,25(OH)2D3 的影响。 公众健康相关性：维生素 D 对于维持骨骼健康非常重要。在这个项目中，我们将通过研究维生素及其受体在模型生物（发育中的斑马鱼）中的作用来研究维生素及其受体在骨骼和软骨中的作用。通过研究活性维生素 D 及其受体对影响骨骼发育的生长因子的影响，我们将深入了解维生素在骨骼中的功能。这些信息将有助于预防因衰老而发生的骨质流失以及治疗骨质疏松症。

项目成果

Vitamin D and the kidney.

维生素 D 和肾脏。

• 发表时间: 2012-07-01
• 影响因子: 3.9
• 作者: Kumar, Rajiv;Tebben, Peter J;Thompson, James R
• 通讯作者: Thompson, James R

The potassium channel interacting protein 3 (DREAM/KChIP3) heterodimerizes with and regulates calmodulin function.

钾通道相互作用蛋白 3 (DREAM/KChIP3) 与钙调蛋白异二聚化并调节钙调蛋白功能。

• 发表时间: 2012-11-16
• 作者: Ramachandran, Pradeep L;Craig, Theodore A;Atanasova, Elena A;Cui, Gaofeng;Owen, Barbara A;Bergen 3rd, H Robert;Mer, Georges;Kumar, Rajiv
• 通讯作者: Kumar, Rajiv

Serum 25-hydroxyvitamin D concentrations and waning pneumococcal antibody titers among individuals with atopy.

特应性个体的血清 25-羟基维生素 D 浓度和肺炎球菌抗体滴度下降。

• 发表时间: 2013
• 影响因子: 2.8
• 作者: Ryoo, Eell;Kumar, Rajiv;Kita, Hirohito;Juhn, Young J
• 通讯作者: Juhn, Young J

Research resource: whole transcriptome RNA sequencing detects multiple 1α,25-dihydroxyvitamin D(3)-sensitive metabolic pathways in developing zebrafish.

研究资源：全转录组 RNA 测序检测发育中斑马鱼的多个 1α,25-二羟基维生素 D(3) 敏感代谢途径。

• DOI: 10.1210/me.2012-1113
• 发表时间: 2012-06-25
• 期刊: Molecular endocrinology
• 作者: T. Craig;Yuji Zhang;M. McNulty;S. Middha;Hemamalini Ketha;Ravinder J Singh;A. Magis;Cory C. Funk;N. Price;S. Ekker;R. Kumar
• 通讯作者: R. Kumar

The sclerostin-bone protein interactome.

硬化素-骨蛋白相互作用组。

• 发表时间: 2012-01-13
• 影响因子: 3.1
• 作者: Devarajan-Ketha, Hemamalini;Craig, Theodore A.;Madden, Benjamin J.;Bergen, H. Robert, III;Kumar, Rajiv
• 通讯作者: Kumar, Rajiv