Nutrigenomics of Intestinal Vitamin D Action

肠道维生素 D 作用的营养基因组学

基本信息

批准号：
9906893
负责人：
SYLVIA S CHRISTAKOS
金额：
$ 51.78万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906893
关键词：
Address Adult Animal Model Architecture Biochemistry Biology Calcium Cecum Cell Differentiation process Cell Maintenance Characteristics Chromatin Clinic Colitis Colon Coupled Data Dietary Calcium Dihydroxycholecalciferols Distal Elderly Epithelial Cells Equilibrium Excision Foundations Gastric Bypass Gene Expression Genes Genetic Genetic Transcription Genomic approach Genomics Glucuronides Goals Homeostasis Human Ingestion Intestines Knockout Mice Large Intestine Ligands Mediating Metabolism Minerals Molecular Mus Nutrient Nutritional Study Organoids Osteoporosis Patients Physiologic calcification Physiology Postmenopause Process Regulation Regulatory Pathway Research Rickets Risk Role Small Intestines Technology Testing Therapeutic Tight Junctions Time Transgenes Transgenic Mice Transgenic Organisms Translations VDR gene Villus Vitamin D Vitamin D3 Receptor Weaning Wild Type Mouse Woman Work bone bone health bone loss bone mass bone metabolism calcium absorption calcium intake calcium metabolism clinical practice colon cancer prevention epigenomics experimental study functional genomics genome-wide genomic locus high risk population ileum improved innovation intestinal villi mouse model novel novel therapeutic intervention nutrition nutrition related genetics nutritional genomics prevent progenitor receptor expression receptor function receptor-mediated signaling stem cells transcription factor

项目摘要

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.

项目摘要维生素D的最重要功能是调节肠钙滥用 - 经典的作用维生素D对骨骼健康至关重要。尽管维生素D在肠中的重要性，但维生素的机制肠道中的D行动尚不清楚。尽管大多数CA抽象研究都集中在近端小肠，我们使用盘式肠道特异性敲除（KO）或转基因小鼠的新型初步数据显示了一个 VDR在盘状肠中的重要作用。拟议的研究员工一种基因组方法耦合在新型小鼠模型中的生理研究，以检验以下假设。肠具有控制VDR表达和维生素D作用的独特调节途径，并且钙 VDR靶基因在远端肠中的吸收和表达显着促进骨骼和次要代谢。为了解决这一假设，我们已经开发了两个具体目标。目标1：定义功能 VDR表达和信号传导的基因组学，介导近端和不同肠及其对全身钙和骨代谢的影响。使用全基因组方法我们将识别空间（近端与盘状肠；绒毛vs Crypt）和临时性（pre vs dof tof weeling; Young vs vs vs 成人）对VDR基因基因座染色质结构的影响，以鉴定VDR的关键上游调节剂近端和远端肠中的表达。接下来，近端和远端肠中的VDR靶基因以及祖细胞与分化细胞将在全基因组范围内鉴定。 VDR目标的人类相关性以及使用人类衍生的器官培养物的研究中，将确定VDR调节机制。最后，我们将检验以下假设：远端肠中的CA滥用对骨骼和使用独特的动物模型，包括具有VDR的转基因表达的独特动物模型的矿物质代谢在远端肠道中。我们还将首次确定VDR缺失在整个肠道中的效果或在成年小鼠的钙和骨代谢中特别具体。目标2：确定靶向远端肠子以改善钙平衡和保护骨骼的转化潜力。我们将测试靶向盘式肠吸收能力是否可以是最大化CA的有效方法抽象并最大程度地减少成人骨质流失。这将使用vdr的变换增强表达在远端肠和天然，远端肠目标维生素D形式的使用（25β糖酰苷1,25（OH）2d3）至改善钙平衡并防止骨质流失。这项拟议的研究对PA-16-332有反应 “营养和营养研究方法进行营养研究。”它结合了维生素D的专业知识生物学，营养和基因组学确定如何利用维生素D的分子作用来改善 ca状态的组中有加速骨质流失和骨质疏松症的风险。