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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.

项目概要维生素 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 D 的作用机制 D在肠道中的作用尚不清楚。尽管大多数 Ca 吸收研究都集中在近端小肠，我们使用远端肠特异性敲除（KO）或转基因小鼠的新初步数据揭示了 VDR 在远端肠道中发挥着重要作用。拟议的研究采用基因组方法结合在新型小鼠模型中进行生理学研究，以检验以下假设：肠道具有控制 VDR 表达和维生素 D 作用的独特调节途径，并且钙远端肠道中 VDR 靶基因的吸收和表达对骨骼和矿物质有显着贡献代谢。为了解决这个假设，我们制定了两个具体目标。目标 1：定义泛函介导近端和远端钙吸收的 VDR 表达和信号传导的基因组学肠道及其对全身钙和骨代谢的影响。使用全基因组方法，我们将识别空间（近端肠道与远端肠道；绒毛与隐窝）和时间（断奶前与断奶后；年轻与成人）对 Vdr 基因位点染色质结构的影响，以确定 Vdr 的关键上游调节因子在近端和远端肠中表达。接下来，VDR 的目标基因位于近端和远端肠道以及祖细胞与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源类器官培养物的研究中确定。最后，我们将检验以下假设：远端肠道的钙吸收对骨骼和骨骼的影响显着。使用独特的动物模型（包括仅转基因表达 VDR 的 VDR KO 小鼠）进行矿物质代谢在远端肠道。我们还将首次确定 VDR 缺失对整个肠道的影响或者特别是在成年小鼠的远端肠道中对钙和骨代谢的影响。目标 2：确定针对远端肠道改善钙平衡和保护骨骼的转化潜力。我们将测试以远端肠道的吸收能力为目标是否可以成为最大化 Ca 的有效方法吸收并最大限度地减少成人骨质流失。这将使用 VDR 的转基因增强表达来完成远端肠道并使用天然的远端肠道靶向维生素 D 形式（25 β 葡萄糖醛酸 1,25(OH)2D3）改善钙平衡并防止骨质流失。这项拟议的研究响应 PA-16-332 “营养遗传学和营养基因组学方法的营养研究。”它结合了维生素 D 方面的专业知识生物学、营养学和基因组学，以确定如何利用维生素 D 的分子作用来改善处于加速骨质流失和骨质疏松症风险人群中的钙状态。