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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

基本信息

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
项目类别：
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

项目摘要

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）在组织中的功能，其中它在跨上皮钙（Ca）和磷酸盐（Pi）运输（“非经典”效应）中没有作用，使用斑马鱼，Danio rerio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软骨的发育和成熟。在目的1中，我们将研究1,25 (OH)2D3对小鼠骨骼发育的影响。我们将在发育中的斑马鱼胚胎中注射1a，25(OH)2D3，以确定1a，25(OH)2D3是否会改变BMP和BMP受体表达、BMP信号传导、软骨发育和骨骼形态。在目标2中，我们将利用反义morpholino寡核苷酸方法确定在发育中的斑马鱼胚胎中“敲低”VDR表达的效果。我们将评估VDR基因敲除对斑马鱼胚胎BMP和BMP受体表达、BMP信号传导、软骨发育和骨骼形态的影响。意义：1a，25(OH)2D3及其受体对钙转运的影响已经在哺乳动物和人类中得到了广泛的研究。然而，与钙转运无关的效应尚未被详细研究。通过检查1a，25(OH)2D3和VDR通过BMP通路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对软骨的直接和不依赖钙的影响。我们还将建立斑马鱼作为一种新的模式生物，以检验1a，25(OH)2D3的影响。