Nutrigenomics of Intestinal Vitamin D Action

项目摘要 维生素D最重要的功能是调节肠道钙吸收--这是维生素D的经典作用 维生素D对骨骼健康至关重要。尽管维生素D在肠道中很重要，但维生素的作用机制 D在肠道中的作用尚不清楚。虽然大多数钙吸收的研究都集中在近端小的 肠，我们使用远端肠道特异基因敲除(KO)或转基因小鼠的新的初步数据揭示了 VDR在远端肠道中的重要作用。这项拟议的研究采用了基因组学方法 在新的小鼠模型中进行生理学研究，以检验以下假设 肠道有控制VDR表达和维生素D作用独特调节通路，以及钙 VDR靶基因在远端肠道的吸收和表达对骨和矿物质有重要贡献 新陈代谢。为了解决这一假设，我们制定了两个具体目标。目标1：定义功能 近端和远端VDR表达和信号调节钙吸收的基因组学研究 肠道及其对全身钙和骨代谢的影响。使用全基因组方法，我们 将确定空间(近端与远端肠道；绒毛与隐窝)和时间(断奶前与断奶后；年轻与 成人)对VDR基因座染色质结构的影响以识别VDR的关键上游调控因子 在近端和远端肠道中表达。接下来，VDR靶基因在近端和远端肠道以及在 祖细胞和分化细胞将在全基因组范围内进行鉴定。VDR目标的人类相关性 以及VDR调节机制将在使用人类衍生有机物培养的研究中确定。 最后，我们将检验这一假说，即远端肠道中的钙吸收对骨骼和 利用独特的动物模型进行矿物质代谢，包括仅表达VDR转基因的VDR KO小鼠 在远端的肠道里。我们还将首次确定VDR缺失对整个肠道的影响 或特别是在成年小鼠的远端肠道对钙和骨代谢的影响。目标2：确定 靶向远端肠道以改善钙平衡和保护骨骼的翻译潜力。我们 将测试以远端肠道的吸收能力为目标是否是最大化病例的有效方法 吸收并最大限度地减少成人的骨质流失。这将通过转基因增强的VDR在 远端肠道和使用天然的远端肠道靶向维生素D形式(25β葡萄糖醛酸苷1，25(OH)2D3)以 改善钙平衡，防止骨质流失。这项拟议的研究是对PA-16-332的响应 营养学研究的营养遗传学和营养基因组学方法。它结合了维生素D的专业知识 生物学、营养学和基因组学，以确定如何利用维生素D的分子作用来改善 有加速骨质流失和骨质疏松风险的人群中的CA状态。

Project Summary The most important function of vitamin D is the regulation of intestinal calcium absorption – a classical role of vitamin D critical for bone health. Despite the importance of vitamin D in the intestine, the mechanisms of vitamin D action in intestine are not clear. Although most Ca absorption research has focused on the proximal small intestine, our novel preliminary data using distal intestine specific knockout (KO) or transgenic mice reveal an essential role for VDR in the distal intestine. The proposed research employs a genomic approach coupled to physiology studies in novel mouse models to test the hypothesis that the proximal and distal segments of the intestine have unique regulatory pathways controlling VDR expression and vitamin D action, and that calcium absorption and expression of VDR target genes in the distal intestine contribute significantly to bone and mineral metabolism. To address this hypothesis we have developed two specific aims. Aim 1: Define the functional genomics of VDR expression and signaling that mediate calcium absorption in the proximal and distal intestine and its impact on whole body calcium and bone metabolism. Using a genome-wide approach we will identify spatial (proximal vs distal intestine; villus vs crypt) and temporal (pre vs post weaning; young vs adult) effects on chromatin architecture of the Vdr gene locus to identify critical upstream regulators of Vdr expression in proximal and distal intestine. Next, VDR target genes in the proximal and distal intestine and in progenitor vs differentiated cells will be identified on a genome-wide scale. The human relevance of VDR targets as well as VDR regulatory mechanisms will be determined in studies using human-derived organoid cultures. Finally, we will test the hypothesis that Ca absorption in the distal intestine contributes significantly to bone and mineral metabolism using unique animal models including VDR KO mice with transgenic expression of VDR only in the distal intestine. We will also determine for the first time the effect of VDR deletion throughout the intestine or specifically in the distal intestine in adult mice on calcium and bone metabolism. Aim 2: Determine the translational potential of targeting the distal intestine to improve calcium balance and protect bone. We will test whether targeting the absorptive capacity of the distal intestine can be an effective way to maximize Ca absorption and minimize adult bone loss. This will be done using transgene-enhanced expression of VDR in the distal intestine and use of a natural, distal intestine-targeted vitamin D form (25 β glucuronide 1,25(OH)2D3) to improve calcium balance and protect against bone loss. This proposed research is responsive to PA-16-332 “Nutrigenetics and Nutrigenomics Approaches for Nutrition Research.” It combines expertise in vitamin D biology, nutrition, and genomics to determine how the molecular actions of vitamin D can be utilized to improve Ca status in groups at risk for accelerated bone loss and osteoporosis.