Diet by Gene Interactions Affecting Calcium and Bone Metabolism

基因相互作用影响钙和骨代谢的饮食

• 批准号: 7706591
• 负责人: James C. Fleet
• 金额: $ 37.69万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706591
• 关键词: Address; Adult; Affect; Age; Alleles; Animal Model; Biological; Biology; Bone Density; Bone Diseases; Calcium; Candidate Disease Gene; Collaborations; Complex; Development; Diet; Dietary Calcium; Dietary Factors; Dihydroxycholecalciferols; Elderly; Environment; Environmental Risk Factor; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetic Variation; Genotype; Goals; Grant; Habits; Health; Human; Inbred Mouse; Individual; Inherited; Initiator Codon; Intake; Intestines; Knock-in Mouse; Knockout Mice; Lead; Metabolism; Minerals; Modeling; Mus; Mutation; Osteoblasts; Osteoporosis; Osteoporosis prevention; Persons; Physiological; Physiological Adaptation; Population; Positioning Attribute; Prevention; Protein Isoforms; Proteins; Recombinants; Recommendation; Recording of previous events; Research; Risk; Serum; Staging; Stress; System; Testing; Transgenic Mice; VDR gene; Vitamin D3 Receptor; bone; bone health; bone loss; bone mass; bone metabolism; calcium absorption; calcium intake; calcium metabolism; disorder risk; gene environment interaction; gene interaction; genetic variant; lifestyle factors; mouse model; nutrient metabolism; osteoporosis with pathological fracture; preclinical study; public health relevance; response

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.

描述（由申请人提供）：骨质疏松症是老年人的严重健康问题，预计随着美国人口老龄化，骨质疏松症将变得更加普遍。像许多复杂的生理系统一样，骨生物学依赖于遗传因素和环境因素，如饮食。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剂，或者它们的作用是否是协同作用的。我们的长期目标是确定影响个体对低膳食钙摄入的反应的遗传变异，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，我们有两个通用的基因x环境（GXE）相互作用模型，我们将测试。第一个模型预测，高骨量基因型的益处需要高膳食钙摄入量的存在才能实现（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，并确定遗传变异，影响生理反应不足的膳食钙摄入量，我们已经开发了三个具体的目标（SA）：SA 1：测试是否饮食钙摄入量影响的能力与LRP 5 G171 V多态性的小鼠达到其遗传潜力的高骨量。LPR5是正常成骨细胞发育所必需的，G171V突变导致高骨量。这将直接测试GXE模型1。SA2：开发人源化小鼠模型，以测试人类（维生素D受体）VDR基因中FokI起始密码子多态性的活性较低的“f”等位基因是否使这些小鼠对膳食钙缺乏对骨骼的负面影响更敏感。VDR的较长的“f”形式被认为比较短的“F”等位基因转录活性低，这将使小鼠人源化为具有“f”形式，不太能够适应增加血清1，25二羟基维生素D水平（钙代谢的主要调节剂）的低钙饮食。我们将创建具有这两种VDR同种型的人源化小鼠，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：利用正向遗传学方法在BXD重组近交系（RI）小鼠群体中鉴定影响骨代谢和钙代谢对膳食钙限制反应差异的QTL。我们将使用BXD RI面板来表征骨密度和肠道钙吸收对膳食钙限制的反应。这些研究将确定含有候选基因多态性的QTL，可以在未来的研究中进行检查。我们的实验室有很好的条件进行这三个目标的研究，因为它有很长的历史，使用小鼠模型研究膳食钙对骨和矿物质代谢的影响。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至关重要。有些人认为，骨质疏松症预防信息应该只针对那些遗传基因使他们“处于危险之中”的人，即高膳食钙摄入量可能只会使美国人口的一部分受益。然而，膳食钙摄入量和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。