Nutrigenetics of Intestinal Ca Absorption

项目总结： 饮食遗传(GxD)的相互作用影响钙的吸收，并影响青少年达到 峰值骨量(PBM)是终身预防骨质疏松症的关键参数。我国居民膳食钙摄入量偏低 儿童可以限制PBM，但生理适应将饮食中低钙摄入量的后果降至最低 通过提高骨骼中维生素D调节的肠道钙吸收效率。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。我们使用连锁图谱来识别 BXD重组近交系小鼠生长发育过程中钙和骨代谢的新遗传位点。我们 提出新的研究以确定影响肠道钙吸收的功能多态。之后我们 将在小鼠模型中验证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：确定表达水平的QTL (EQTL)控制BXD RI小鼠钙吸收的基因。两种方法将是 用于识别影响基因转录和信使核糖核酸稳定性的非编码多态。这些数据将 与atac-seq数据集成，并与生物信息学工具相结合，以识别调控位点的多态 影响钙吸收。目标2：确定通过基因定位确定的特定基因在 基础钙吸收的控制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将改变基础钙吸收。我们对五个基因进行了优先排序 从我们的基因图谱研究中识别出的基因座来验证这一假说。删除这两个基因等位基因将测试 对于该基因在钙吸收中的重要作用，当缺失一个等位基因时，将模拟部分丢失 当多态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。目的3：确定候选基因多态性对人体钙吸收的影响。 青春期的男孩女孩。我们将鉴定和测试小鼠的人类同源基因的功能多态性 我们使用580名青少年受试者的钙吸收和基因数据进行定位研究，确定了基因。 我们研究团队的专业知识、我们独特的初步数据以及我们新颖的样本库存使我们能够 了解PBM-钙吸收的一个关键生理决定因素的遗传控制-及其主要 调节剂-钙摄入量。我们已经发现了控制钙吸收的新基因，我们有工具来 在老鼠模型中验证它们，然后将这些信息翻译给人类青少年。完成后， 我们的发现有可能确定影响膳食钙推荐摄入量的遗传因素 人类的峰值骨量。

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.