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（由申请人提供）：维生素D（1,25（OH）2D）的主动形式调节骨，肾脏和肠道中的事件以控制全身CA代谢并影响水骨病的发展。几条证据表明，Ca吸收在骨质疏松发育中的作用需要额外关注：随着衰老和绝经后骨折后，CA的吸收效率降低了；低分数Ca的吸收与绝经后妇女的髋部骨折风险增加有关，并且在老年人和绝经后妇女中对1,25（OH）2 D的作用的肠道耐药性产生。我的研究的长期目标是了解导致低分数Ca吸收的细胞机制，并降低导致骨质疏松症的肠道维生素D作用。提议解释维生素D调节CA吸收的模型的许多方面尚未测试。该提案反映了我们对肠上皮细胞中维生素D作用的机械理解的演变，以及我们对将基本研究结果转化为全身CA代谢的复杂生理学的兴趣。我们的具体目的是：（1）评估VDR位置和水平在控制肠吸收中的重要性。我们将使用遗传改良的小鼠来测试是否可以防止与年龄相关的钙吸收不良和肠道维生素D耐药性（Subaim1a），并且我们将确定VDR的vdr特异性缺失是否特异性地从肠球菌，CECUM和结肠中可以改变整个体内钙的钙代谢（subaim1b），（subaim1b）（2）是否是偶然的（2）（2）（2）（2）（2）吸收和吸收。我们将使用转基因的小鼠来确定肠道TRPV6是否可以恢复VDR无效表型并防止随着衰老的衰老降低Ca吸收，（3）确定控制肠细胞中维生素D介导的基因激活的因子。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）和细胞研究中的主动作用，以评估核内VDR运动和启动子动力学在维生素D介导的基因转录中发挥作用的作用（Subaim 3B）。我们的位置是检验这些假设的独特位置，并扩展我们对维生素D调节CA吸收的理解有助于保护骨骼健康。我们的工作将为优化CA吸收和预防骨质疏松症的策略提供临床前证据。公共卫生相关性：饮食钙对于骨骼健康和预防骨骼疾病骨质疏松症至关重要。不幸的是，随着衰老和更年期，肠道吸收饮食钙的能力会降低。维生素D是肠钙吸收的主要调节剂，但许多因素可能会损害维生素D作用。我们将进行机械和转化研究，以研究维生素D如何影响肠道钙吸收。我们的重点将放在通过结合维生素D（维生素D受体的蛋白质）发生的事件。这项工作将为开发预防骨质疏松症的策略奠定基础，以最大化肠道中的维生素D作用并优化饮食钙的吸收。