Nutrigenetics of Intestinal Ca Absorption

肠道钙吸收的营养遗传学

• 批准号: 10017177
• 负责人: James C. Fleet
• 金额: $ 45.64万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017177
• 关键词: ATAC-seq; Adolescence; Adolescent; Affect; Alleles; Binding Sites; Candidate Disease Gene; Child; Childhood; Chromosome Mapping; Clinical Trials; Complex; Consumption; Coupled; Data; Databases; Diet; Duodenum; Equipment and supply inventories; Female Adolescents; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Growth; Human; Inbred Mouse; Intake; Intestines; Male Adolescents; Membrane Transport Proteins; Metabolism; Modeling; Mus; Nutrient; Nutritional Science; Nutritional Study; Orthologous Gene; Osteoporosis prevention; Parents; Physiological; Physiological Adaptation; Physiology; Publishing; Quantitative Trait Loci; RNA; Recombinants; Recommendation; Regulation; Research; Resources; Role; Sampling; Serum; Site; Stimulus; Testing; Thyroid Hormones; Translating; Untranslated RNA; Vitamin D; Vitamin D3 Receptor; Work; absorption; bioinformatics tool; bone; bone health; bone mass; bone metabolism; calcium absorption; experimental study; gene discovery; genomic locus; hormone metabolism; innovation; mRNA Stability; mouse model; novel; nutrition; nutrition related genetics; nutritional genomics; phenotypic data; response; tool; transcription factor

Project Summary: Genetics-by-diet (GxD) interactions affect Ca absorption and influence the ability of adolescents to reach peak bone mass (PBM), a critical parameter for lifelong osteoporosis prevention. Low dietary Ca intake in children can limit PBM but physiological adaptation minimizes the consequence of low dietary Ca intake on bone by increasing vitamin D-regulated intestinal Ca absorption efficiency. Our long-term goal is to understand how genetics and diet interact to affect Ca metabolism and bone health. We used linkage mapping to identify novel genetic loci controlling of Ca and bone metabolism in growing BXD recombinant inbred mouse lines. We propose new studies to identify the functional polymorphisms affecting intestinal Ca absorption. Afterwards we will validate the contribution of several candidate genes in mouse models and translate these findings to humans. To meet our goals we have developed three specific aims: Aim 1: Identify expression level QTL (eQTL) in duodenum that underly the loci controlling Ca absorption in BXD RI mice. Two approaches will be used to identify non-coding polymorphisms that affect gene transcription and mRNA stability. These data will be integrated with ATAC-seq data and coupled to bioinformatics tools to identify regulatory site polymorphisms affecting Ca absorption. Aim 2: Determine the role of specific genes identified by genetic mapping to the control of basal Ca absorption and its adaptation to low dietary Ca intake. We hypothesize that polymorphisms affecting gene expression will modify basal Ca absorption. We have prioritized five genes identified within loci from our genetic mapping study to test this hypothesis. Deleting both gene alleles will test for an essential role of the gene in Ca absorption while deleting one allele will model the partial loss of expression that occurs when polymorphisms affect transcription factor binding sites. Finally, we hypothesize that the impact of disrupting these genes will be accentuated when low Ca diets increase intestinal Ca absorption efficiency. Aim 3: Determine the impact of candidate gene polymorphisms on Ca absorption in adolescent boys and girls. We will identify and test functional polymorphisms in the human orthologs of mouse genes identified in our mapping studies using Ca absorption and genotype data from 580 adolescent subjects. The expertise of our research team, our unique preliminary data, and our novel sample inventory enables us to understand the genetic controls of a critical physiologic determinant of PBM - Ca absorption – and its major regulator – Ca intake. We have identified novel genes controlling Ca absorption and we have the tools to validate them in mouse models and then translate this information to human adolescents. Upon completion, our findings have potential to define genetic factors that influence dietary Ca recommendations for achieving peak bone mass in humans.

项目摘要： 遗传学by-diet（GXD）相互作用会影响CA抽象并影响青少年到达的能力 峰骨量（PBM），这是预防终身骨质疏松症的关键参数。低饮食摄入量 儿童可以限制PBM，但身体适应可最大程度地减少饮食中摄入量低的后果 通过增加维生素D调节的肠道Ca吸收效率来增加骨骼。我们的长期目标是了解 遗传学和饮食如何相互作用以影响CA代谢和骨骼健康。我们使用链接映射来识别 新的遗传基因座控制Ca和骨代谢在生长的BXD重组小鼠系中。我们 提出新的研究，以确定影响肠道CA抽象的功能多态性。之后我们 将验证几个候选基因在小鼠模型中的贡献，并将这些发现转化为 人类。为了满足我们的目标，我们已经开发了三个具体目标：目标1：确定表达水平qtl （EQTL）在DuodeNum中，在BXD RI小鼠中控制Ca吸收的基因座中。两种方法将是 用于鉴定影响基因转录和mRNA稳定性的非编码多态性。这些数据将 与ATAC-SEQ数据集成并与生物信息学工具结合起来，以识别监管部位多态性 影响CA滥用。 AIM 2：确定通过遗传图鉴定的特定基因的作用 控制碱性CA吸收及其对低饮食CA摄入量的适应性。我们假设这一点 影响基因表达的多态性将改变基本的Ca抽象。我们优先考虑五个基因 从我们的基因映射研究中鉴定出基因座，以检验该假设。删除两个基因等位基因将测试 对于该基因在CA滥用中的重要作用，而删除一个等位基因将模拟部分损失 当多态性影响转录因子结合位点时发生的表达。最后，我们假设 当低Ca饮食增加肠道CA时，破坏这些基因的影响将突出 目标3：确定候选基因多态性对CA抽象的影响 青春期男孩和女孩。我们将识别和测试小鼠人类直系同源物中的功能多态性 在我们的映射研究中使用CA抽象和580名青少年受试者的基因型数据鉴定的基因。 我们的研究团队的专业知识，我们独特的初步数据以及我们的小说样本清单使我们能够 了解PBM的关键生理决定因素的遗传控制 - CA滥用 - 其主要 调节器 - 摄入量。我们已经确定了控制CA抽象的新型基因，我们有工具 在鼠标模型中验证它们，然后将此信息转化为人类青少年。完成后， 我们的发现有可能定义影响饮食CA建议的遗传因素 人类的峰值骨量。