Diet by Gene Interactions Affecting Calcium and Bone Metabolism

描述（由申请人提供）：骨质疏松症是老年人严重的健康问题，随着美国人口老龄化，预计将变得更加普遍。像许多复杂的生理系统一样，骨骼生物学既依赖于遗传因素，也依赖于饮食等环境因素。然而，目前尚不清楚遗传和饮食因素是否是骨骼健康的独立调节因素，还是它们的影响是协同的。我们的长期目标是确定影响个体对低钙饮食反应的基因变异，然后将这些信息作为制定个性化饮食建议的基础，以优化骨骼健康。在短期内，我们将测试两个通用的基因x环境（GXE）相互作用模型。第一个模型预测，高骨量基因型的益处需要实现高饮食钙摄入量（即饮食是允许的）。第二个模型预测，控制营养代谢或利用的基因多态性导致个体对膳食钙摄入不足更敏感（即基因型的后果是有条件的）。为了解决这些模型，并确定影响饮食钙摄入不足生理反应的遗传变异，我们制定了三个具体目标（SA）： SA1：测试饮食钙摄入是否影响具有LRP5 G171V多态性的小鼠达到其高骨量的遗传潜力的能力。LPR5对正常成骨细胞发育至关重要，G171V突变导致高骨量。这将直接测试GXE模型1。SA2：建立人源化小鼠模型，测试人类（维生素D受体）VDR基因FokI启动密码子多态性的“f”等位基因活性较低是否会使这些小鼠对膳食钙缺乏对骨骼的负面影响更敏感。较长的“f”型VDR的转录活性低于较短的“f”型等位基因，这将使具有“f”型的小鼠适应低钙饮食的能力降低，而低钙饮食会增加血清125二羟基维生素D水平（钙代谢的主要调节剂）。我们将创建具有这两种VDR异构体的人源化小鼠，以便我们可以在未来的提案中使用它们直接测试GXE模型2。SA3：在BXD重组自交系（RI）小鼠群体中，利用正向遗传学方法鉴定与膳食钙限制对骨和钙代谢的差异反应有关的qtl。我们将使用BXD RI面板来表征骨密度和肠道钙吸收对饮食钙限制的反应。这些研究将确定包含候选基因多态性的qtl，可以在未来的研究中进行检测。我们的实验室在利用小鼠模型研究膳食钙对骨骼和矿物质代谢影响的机制方面有着悠久的历史，因此有能力开展这三个目标的研究。此外，我们已经建立了合作和协会，这将使我们能够进行这些GXE研究所需的仔细分析。公共卫生相关性：遗传因素和生活习惯，如高膳食钙摄入量，对最佳骨骼健康和预防骨质疏松症都是必不可少的。一些人认为，预防骨质疏松症的信息应该只针对那些基因使他们有患这种疾病的“风险”的人，也就是说，高钙饮食摄入可能只对一小部分美国人有益。然而，膳食钙摄入量与一个人的遗传背景之间的关系尚不清楚。我们的研究将使用动物模型详细研究这种关系。

DESCRIPTION (provided by applicant): Osteoporosis is a serious health concern of the elderly that is expected to become more prevalent as the US population ages. Like many complex physiological systems, bone biology is dependent on both genetic factors and environmental factors like diet. It is not clear, however, whether genetic and dietary factors are independent modifiers of bone health or whether their effects are synergistic. Our long-term goal is to identify the genetic variants that influence an individual's response to low dietary calcium intake and then use this information as a foundation for making personalized diet recommendations to optimize bone health. In the short term, we have two general gene x environment (GXE) interaction models that we will test. The first model predicts that the benefits of high bone mass genotypes require the presence of high dietary calcium intake to be realized (i.e. diet is permissive). The second model predicts that polymorphisms in genes controlling nutrient metabolism or utilization lead to individuals that are more sensitive to inadequate dietary calcium intake (i.e. the consequence of genotype is conditional). To address these models, and to identify genetic variation that influences the physiologic response to inadequate dietary calcium intake, we have developed three specific aims (SA): SA1: Test whether dietary Ca intake influences the ability of mice with the LRP5 G171V polymorphism to reach their genetic potential for high bone mass. LPR5 is essential for normal osteoblast development and the G171V mutation causes high bone mass. This will directly test the GXE model 1. SA2: Develop humanized mouse models to test whether the less active "f" allele of the FokI start codon polymorphism in the human (vitamin D receptor) VDR gene make these mice more sensitive to the negative impact of dietary calcium depletion on bone. The longer "f" form of the VDR is proposed to be less transcriptionally active than the shorter "F" allele and this would make mice humanized to have the "f' form less able to adapt to low calcium diets that increase serum 1,25 dihydroxyvitamin D levels (a major regulator of calcium metabolism). We will create mice humanized to have these two VDR isoforms so that we can use them in future proposals to directly test GXE model 2. SA3: To use forward genetics in the BXD recombinant inbred (RI) mouse panel to identify QTLs responsible for differential responses of bone and calcium metabolism to dietary calcium restriction. We will use the BXD RI panel to characterize the response of bone density and intestinal calcium absorption to dietary calcium restriction. These studies will identify QTLs that contain candidate gene polymorphisms that can be examined in future studies. Our lab is well positioned to conduct the research in these three aims due to its long history of mechanistic studies on the impact of dietary calcium on bone and mineral metabolism using mouse models. In addition, we have developed collaborations and associations that will permit us to conduct the careful analyses needed for these GXE studies. PUBLIC HEALTH RELEVANCE: Both inherited genetic factors and lifestyle habits like high dietary calcium intake are essential for optimal bone health and for the prevention of the bone disease osteoporosis. Some believe that osteoporosis prevention messages should be targeted to only those people whose genetics make them "at risk" for the disease, i.e. high dietary calcium intake may only benefit a subset of the US population. However, the relationship between dietary calcium intake and a person's genetic background isn't clear. Our research will examine this relationship in detail using animal models.