Diet by Gene Interactions Affecting Calcium and Bone Metabolism

描述(由申请人提供)：骨质疏松症是一种严重的老年人健康问题，预计随着美国人口的老龄化，这种疾病将变得更加普遍。像许多复杂的生理系统一样，骨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修饰者，或者它们的影响是否具有协同作用。我们的长期目标是确定影响个人对低钙饮食摄入量反应的基因变异，然后利用这些信息作为提出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)交互模型。第一个模型预测，高骨量基因型的好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，控制营养新陈代谢或利用的基因的多态导致个体对膳食钙摄入量不足更敏感(即，基因型的结果是有条件的)。为了解决这些模型，并确定影响饮食钙摄入量不足的生理反应的遗传变异，我们制定了三个特定目标(SA)：SA1：测试饮食钙摄入量是否影响LRP5 G171V多态小鼠发挥其高骨量遗传潜力的能力。LPR5对正常的成骨细胞发育是必不可少的，而G171V突变会导致骨量增加。这将直接测试GxE模型1.SA2：开发人源化的小鼠模型，以测试人类(维生素D受体)VDR基因中FokI起始密码子多态的不太活跃的“f”等位基因是否使这些小鼠对饮食钙耗竭对骨骼的负面影响更加敏感。较长的“f”形式的VDR在转录上的活性低于较短的“F”等位基因，这将使“f‘形式的小鼠更不能适应低钙饮食，从而增加血清1，25-二羟基维生素D水平(钙代谢的主要调节因子)。我们将创建具有这两种VDR亚型的人源化小鼠，以便我们可以在未来的提案中使用它们来直接测试GxE模型2。SA3：在BXD重组近交系(RI)小鼠小组中使用正向遗传学来识别负责骨和钙代谢对饮食钙限制的差异反应的QTL。我们将使用BXD RI小组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的QTL，可以在未来的研究中进行检查。由于我们实验室长期使用小鼠模型研究膳食钙对骨骼和矿物质代谢的影响，因此我们的实验室处于有利地位，可以在这三个目标上进行研究。此外，我们还建立了合作和联系，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：遗传遗传因素和生活方式习惯，如高饮食钙摄入量，对于最佳的骨骼健康和预防骨质疏松症至关重要。一些人认为，预防骨质疏松症的信息应该只针对那些遗传使他们处于患病风险中的人，即饮食中高钙摄入量可能只会使美国人口中的一部分受益。然而，饮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.