Intestinal Calcium Absorption: Molecular Mechanism

肠道钙吸收：分子机制

• 批准号: 8011274
• 负责人: James C. Fleet
• 金额: $ 10万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-25 至 2011-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011274
• 关键词: Age; Aging; Androgen Receptor; Animals; Apical; Attention; Bone Diseases; Calcium; Calcium Channel; Cecum; Cells; Colon; Complex; Data; Development; Dietary Calcium; Diffusion; Elderly; Enterocytes; Estrogens; Event; Evolution; Foundations; Fracture; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucocorticoids; Goals; Hip Fractures; Homeostasis; Hormones; Human; Intestines; Kidney; Kinetics; Knockout Mice; Life; Ligand Binding; Ligands; Location; Maintenance; Malabsorption Syndromes; Mediating; Menopause; Modeling; Molecular; Molecular Chaperones; Movement; Mus; Nutrient; Osteoporosis; Osteoporosis prevention; Peripheral; Phase; Phenotype; Phosphorylation; Phosphotransferases; Physiology; Play; Positioning Attribute; Postmenopause; Prevention; Prevention strategy; Process; Proliferating; Proteins; Regulation; Relative Risks; Research; Resistance; Retinoid X Receptor alpha; Risk; Role; Signal Transduction; Small Intestines; Stress; Testing; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Translating; Vitamin D; Vitamin D-Binding Protein; Vitamin D3 Receptor; Woman; Work; absorption; aged; apical membrane; base; bone; bone health; bone mass; calcium absorption; calcium intake; calcium metabolism; fundamental research; ileum; in vivo; interest; member; physiologic model; pre-clinical; prevent; promoter; public health relevance; rapid growth; receptor; receptor expression; receptor function; response; spine bone structure; steroid hormone receptor; translational study; uptake

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.

描述（申请人提供）：维生素 D 的活性形式（1,25(OH)2D）可调节骨骼、肾脏和肠道的活动，从而控制全身钙代谢并影响骨质疏松症的发展。多项证据表明，钙吸收在骨质疏松症发展中的作用需要额外关注：随着年龄的增长以及患有骨折的绝经后妇女，钙吸收效率会降低；钙吸收分数低与绝经后妇女髋部骨折风险增加有关，并且老年人和绝经后妇女肠道对 1,25(OH)2 D 作用产生抵抗力。我研究的长期目标是了解导致骨质疏松症的钙吸收分数低和肠道维生素 D 作用减少的细胞机制。为解释维生素 D 调节的钙吸收而提出的模型的许多方面尚未经过测试。该提案反映了我们对肠上皮细胞中维生素 D 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。我们的具体目标是：（1）评估VDR位置和水平在控制肠道Ca吸收中的重要性。我们将使用转基因小鼠来测试高肠道 VDR 是否可以预防与年龄相关的钙吸收不良和肠道维生素 D 抵抗 (subaim1a)，并且我们将确定从回肠、盲肠和结肠中特异性删除 VDR 是否可以改变全身钙代谢（subaim1b），（2）确定顶膜Ca通道TRPV6是否对于肠道Ca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无效表型并防止随着年龄的增长而导致钙吸收的丧失，（3）确定控制肠上皮细胞中维生素D介导的基因激活的因素。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 (subaim 3a) 中的积极作用，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 (subaim) 中的作用3b).我们拥有独特的优势来检验这些假设，并加深我们对维生素 D 调节钙吸收如何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症的策略提供临床前证据。公众健康相关性：膳食钙对于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衰老和更年期而降低。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，以研究维生素 D 如何影响肠道钙吸收。我们的重点是通过与维生素 D 结合的蛋白质（维生素 D 受体）发生的事件。这项工作将为制定骨质疏松症预防策略奠定基础，从而最大限度地发挥维生素 D 在肠道中的作用并优化膳食钙的吸收。