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.

项目概要： 饮食遗传学 (GxD) 相互作用会影响钙吸收并影响青少年达到目标的能力 峰值骨量（PBM），是终生预防骨质疏松症的关键参数。膳食钙摄入量低 儿童可以限制 PBM，但生理适应可最大限度地减少膳食钙摄入量低对身体的影响。 骨通过增加维生素D调节肠道Ca吸收效率。我们的长期目标是了解 遗传和饮食如何相互作用影响钙代谢和骨骼健康。我们使用链接映射来识别 在生长的 BXD 重组近交小鼠系中控制 Ca 和骨代谢的新遗传位点。我们 提出新的研究来确定影响肠道钙吸收的功能多态性。之后我们 将验证小鼠模型中几个候选基因的贡献，并将这些发现转化为 人类。为了实现我们的目标，我们制定了三个具体目标： 目标 1：确定表达水平 QTL (eQTL) 位于十二指肠中，位于控制 BXD RI 小鼠 Ca 吸收的位点之下。两种方法将是 用于识别影响基因转录和 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以识别调控位点多态性 影响钙的吸收。目标 2：确定通过遗传图谱鉴定的特定基因的作用 控制基础钙吸收及其对低膳食钙摄入量的适应。我们假设 影响基因表达的多态性会改变基础钙吸收。我们优先考虑了五个基因 从我们的基因图谱研究中鉴定出基因座来检验这一假设。删除两个基因等位基因将测试 因为该基因在 Ca 吸收中起着重要作用，而删除一个等位基因将模拟 Ca 的部分丧失 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 当低钙饮食增加肠道钙时，破坏这些基因的影响将会加剧 吸收效率。目标 3：确定候选基因多态性对钙吸收的影响 青春期的男孩和女孩。我们将鉴定并测试小鼠的人类直系同源物的功能多态性 我们利用来自 580 名青少年受试者的 Ca 吸收和基因型数据进行绘图研究，确定了基因。 我们研究团队的专业知识、独特的初步数据和新颖的样品库存使我们能够 了解 PBM 的一个关键生理​​决定因素（钙吸收）的遗传控制及其主要因素 调节剂——钙摄入量。我们已经确定了控制钙吸收的新基因，并且我们有工具 在小鼠模型中验证它们，然后将这些信息转化为人类青少年。完成后， 我们的研究结果有可能确定影响膳食钙建议的遗传因素，以实现 人类的骨量峰值。