Intestinal Calcium Absorption: Molecular Mechanism

项目摘要： 活性形式的维生素D（1，25（OH）2D）调节骨骼、肾脏和肠道中的事件，以控制整个身体 钙代谢及影响骨质疏松症的发生。几条证据表明， 钙吸收在骨质疏松症发展中的作用需要额外的关注：钙吸收效率是 随着年龄的增长和绝经后妇女骨折减少;低分数钙吸收已被 与绝经后妇女髋部骨折风险增加和肠道对该作用的抵抗力有关 1，25（OH）2 D在老年人和绝经后妇女中发生。我研究的长期目标是 是为了了解导致低钙吸收率和减少肠道钙吸收的细胞机制。 维生素D的作用，有助于骨质疏松症。许多方面的模型提出来解释维生素 尚未测试D调节的Ca吸收。这一建议反映了我们的机械的演变 了解维生素D在肠上皮细胞中的作用，以及我们对基础研究的兴趣 研究发现了全身钙代谢的复杂生理学。我们的具体目标是：（1）评估 VDR的位置和水平在控制肠道钙吸收中的重要性。我们将利用基因 改良小鼠，以测试高肠道VDR是否可以预防与年龄相关的钙吸收不良和肠道 维生素D抗性（subaim 1a），我们将确定是否从回肠特异性缺失VDR， 盲肠和结肠可改变全身钙代谢（subaim 1b），（2）确定心尖部是否 膜钙通道TRPV 6是肠钙摄取和吸收所必需的。我们将使用 基因修饰小鼠以确定肠TRPV 6是否可以恢复VDR无效表型， （3）确定维生素D介导的基因调控因素 肠细胞中的活化。我们将进行细胞和动物研究，以确定RXR的积极作用， VDR介导的基因转录（子目的3a）和细胞研究，以评估核内VDR 运动和启动子开关动力学在维生素D介导的基因转录中起作用（子目的3b）。我们 独特的定位来测试这些假设，并扩大我们对维生素D如何调节钙的理解。 吸收有助于保护骨骼健康。我们的工作将提供临床前证据的策略，以优化钙 吸收，预防骨质疏松。

Project Summary: The active form of vitamin D (1,25(OH)2D) regulates events in bone, kidney and intestine to control whole body Ca metabolism and influence the development of osteroporosis. Several lines of evidence suggest that the role of Ca absorption in osteoporosis development requires additional attention: Ca absorption efficiency is reduced with aging and in post-menopausal women with fractures; low fractional Ca absorption has been associated with increased hip fracture risk in post-menopausal women, and intestinal resistance to the action of 1,25(OH)2 D develops in the elderly and in post-menopausal women. The long-term goal of my research is to understand the cellular mechanisms causing low fractional Ca absorption and reduced intestinal vitamin D action that contribute to osteoporosis. Many aspects of the models proposed to explain vitamin D-regulated Ca absorption have not been tested. This proposal reflects the evolution of our mechanistic understanding of vitamin D action in the enterocyte and our interest in translating fundamental research findings into the complex physiology of whole body Ca metabolism. Our specific aims are: (1) To assess the importance of VDR location and level in the control of intestinal Ca absorption. We will use genetically modified mice to test if high intestinal VDR can prevent age-associated calcium malabsorption and intestinal vitamin D resistance (subaim1a) and we will determine whether the deletion of VDR specifically from the ileum, cecum, and colon can alter whole body calcium metabolism (subaim1b), (2) To determine whether the apical membrane Ca channel TRPV6 is essential for intestinal Ca uptake and absorption. We will use genetically modified mice to determine whether intestinal TRPV6 can recover the VDR null phenotype and prevent loss of Ca absorption with aging, (3) To determine the factors controlling vitamin D-mediated gene activation in enterocytes. We will conduct cell and animal studies to determine the active role RXR¿ has in VDR mediated gene transcription (subaim 3a) and cell studies to assess the role that intranuclear VDR movement and promoter on-off kinetics plays in vitamin D-mediated gene transcription (subaim 3b). We are uniquely positioned to test these hypotheses and to expand our understanding of how vitamin D regulated Ca absorption helps protect bone health. Our work will provide preclinical evidence for strategies to optimize Ca absorption and prevent osteoporosis.