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，随着美国人口年龄的增长，预计将变得更加普遍。像许多复杂的生理系统一样，骨骼生物学都取决于遗传因素和饮食等环境因素。但是，尚不清楚遗传因素和饮食因素是否是骨骼健康的独立修饰符，还是它们的作用是协同作用。我们的长期目标是确定影响个人对低饮食钙摄入量的反应的遗传变异，然后使用此信息作为提出个性化饮食建议以优化骨骼健康的基础。在短期内，我们有两个通用基因X环境（GXE）相互作用模型，我们将测试。第一个模型预测，高骨质量基因型的益处需要实现高饮食的摄入量（即饮食是允许的）。第二个模型预测，控制养分代谢或利用的基因中的多态性导致对饮食不足的钙摄入量更敏感的个体（即基因型的结果是条件）。为了解决这些模型，并确定影响对饮食钙摄入量不足的生理反应的遗传变异，我们开发了三个特定目标（SA）：SA1：测试饮食CA摄入是否影响LRP5 G171V多态性的小鼠的能力，以达到高骨质量的遗传潜力。 LPR5对于正常成骨细胞发育至关重要，而G171V突变会导致高骨量。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（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骨骼饮食中钙消耗的负面影响更为敏感。提议VDR的“ F”形式较长，比较短的“ f”等位基因的转录活性较小，这会使小鼠人性化以使“ F'形式较低，无法适应低钙饮食，而低钙饮食会增加血清1,25二羟基伏胺D的水平，以使他们能够使用小鼠来构成这些vr液位。直接测试GXE2。SA3的建议：在BXD重组植物（RI）小鼠面板中使用QTL来确定QTL的质量差异，我们将使用BXD RI量表来限制质量降低，以识别量子的降低。可以在未来的研究中检查的基因多态性。此外，我们开发了合作和协会，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）对于最佳骨骼健康和预防骨骼疾病骨质疏松症都是必不可少的。有些人认为，预防骨质疏松症的信息应仅针对那些遗传学使其对该疾病“有风险”的人，即高饮食钙摄入量只能使美国人群的一部分受益。但是，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。