Intestinal Calcium Absorption: Molecular Mechanism

描述（由申请人提供）：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，控制全身钙代谢，影响骨质疏松症的发展。一些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：钙吸收效率随着年龄的增长和绝经后骨折妇女的降低；低钙吸收分数与绝经后妇女髋部骨折风险增加有关，老年人和绝经后妇女肠道对125 (OH) 2d作用产生耐药性。我研究的长期目标是了解导致钙吸收低和肠道维生素D作用减少的细胞机制，从而导致骨质疏松症。用于解释维生素d调节钙吸收的模型的许多方面尚未经过测试。这一建议反映了我们对维生素D在肠细胞中作用的机制理解的演变，以及我们将基础研究成果转化为全身钙代谢的复杂生理学的兴趣。我们的具体目的是：(1)评估VDR的位置和水平在控制肠道钙吸收中的重要性。我们将使用转基因小鼠来测试高肠道VDR是否可以预防年龄相关的钙吸收不良和肠道维生素D抵抗（subaim1a），我们将确定从回肠、盲肠和结肠特异性地删除VDR是否可以改变全身钙代谢（subaim1b）。(2)确定顶端膜钙通道TRPV6是否对肠道钙的摄取和吸收至关重要。我们将使用转基因小鼠来确定肠道TRPV6是否可以恢复VDR零表型并防止Ca吸收随年龄增长而丧失。(3)确定肠道细胞中维生素d介导的基因激活的控制因素。我们将进行细胞和动物研究，以确定RXR1在VDR介导的基因转录中的积极作用（subaim 3a），并进行细胞研究，以评估核内VDR运动和启动子开关动力学在维生素d介导的基因转录中所起的作用（subaim 3b）。我们有独特的优势来测试这些假设，并扩大我们对维生素D如何调节钙吸收帮助保护骨骼健康的理解。我们的工作将为优化钙吸收和预防骨质疏松的策略提供临床前证据。公共卫生相关性：膳食钙对骨骼健康和预防骨质疏松症至关重要。不幸的是，肠道吸收膳食钙的能力随着年龄和更年期而降低。维生素D是肠道钙吸收的主要调节剂，但许多因素可能会损害维生素D的作用。我们将进行机制和转化研究，以检验维生素D如何影响肠道钙吸收。我们的重点是通过一种结合维生素D的蛋白质，即维生素D受体发生的事件。这项工作将为制定预防骨质疏松症的策略奠定基础，使维生素D在肠道中的作用最大化，并优化膳食钙的吸收。

DESCRIPTION (provided by applicant): 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 RXR1 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. PUBLIC HEALTH RELEVANCE: Dietary calcium is essential for bone health and the prevention of the bone disease osteoporosis. Unfortunately, the ability of the intestine to absorb dietary calcium is reduced with aging and the menopause. Vitamin D is the major regulator of intestinal calcium absorption but many factors may impair vitamin D action. We will conduct mechanistic and translational studies to examine how vitamin D influences intestinal calcium absorption. Our focus will be on events that occur through a protein that binds vitamin D, the vitamin D receptor. This work will lay the foundation for developing osteoporosis prevention strategies that maximize vitamin D action in the intestine and optimize the absorption of dietary calcium.