Genetic controls of mineral consumption

描述（由申请人提供）：这是一个发现负责钙，镁，钾和钠消耗的遗传控制的项目。我们已经确定了几个数量性状基因座（QTL）与这些矿物质的消费。我们建议在这里确定这些QTL的基因。为此，我们将首先产生具有渐渗的含有QTL的染色体片段的小鼠的同类品系。这将使用经典的按基因型选择方法或通过利用最近开发的同源株来完成。作为经典方法的一个例子，我们建议完成同类小鼠品系的生产，该品系在Chr 17上分离出一个QTL，该QTL具有令人印象深刻的高LOD分数，用于CaCl 2偏好（LOD = 45）和糖精偏好（LOD = 100）。作为共体起源方法的一个例子，我们建议产生同源系来分离Chr 5上的QTL，NaCl偏好的LOD得分为8.5。据我们所知，这将是第一个要表征的钠消耗量QTL。一旦同源菌株建立，我们将评估候选基因驻留在同源间隔。这将使用计算机模拟分析、基因表达谱分析和相关方法的组合来完成。如有必要，将记录舔体反应和味觉电生理学，以确定基因作用的位点。目标是将候选基因的列表减少到可以使用基因工程小鼠进行评估的数量。找到负责矿物质消耗的基因将有助于我们理解为什么人们不能摄入令人满意的矿物质。钙、镁和钾的低摄入量以及钠的高摄入量与影响美国人口的许多疾病的病因有关，包括高血压、肥胖症、骨质疏松症和某些形式的癌症。这里提出的研究结果将揭示矿物消费的机制。有了这些知识，就有可能有针对性地采取新的治疗和战略，纠正摄入不足，从而改善或消除疾病。 公共卫生相关性：这是一项发现矿物质消耗的遗传控制的建议。钙、镁和钾的低摄入量以及钠的高摄入量与影响美国人口的许多疾病的病因有关，包括高血压、肥胖症、骨质疏松症和某些形式的癌症。要了解为什么人们不能摄入令人满意的矿物质，找到导致矿物质消耗的潜在基因是至关重要的。该项目提供的信息将阐明我们选择食用含有矿物质的特定食物和饮料的基本机制。这对于指导营养干预措施和政策非常重要。也将有可能有针对性的新的治疗和战略，纠正摄入不足，从而改善或消除疾病。

DESCRIPTION (provided by applicant): This is a project to discover the genetic controls that are responsible for the consumption of calcium, magnesium, potassium and sodium. We have already identified several quantitative trait loci (QTLs) related to consumption of these minerals. We propose here to identify the genes underlying some of these QTLs. To do this, we will first produce congenic strains of mice with introgressed QTL- containing chromosomal fragments. This will be done using either a classic selection-by-genotype approach or by taking advantage of recently developed consomic strains. As an example of the classic approach, we propose to complete production of congenic mouse lines that isolate a QTL on Chr 17 that has impressively high LOD scores for CaCl2 preference (LOD = 45) and saccharin preference (LOD = 100). As an example of the consomic-origin approach, we propose to produce congenic lines to isolate a QTL on Chr 5, with a LOD score for NaCl preference of 8.5. To our knowledge, this will be the first QTL for sodium consumption to be characterized. Once congenic strains are established, we will evaluate candidate genes residing in the congenic interval. This will be done using a combination of in silico analyses, gene expression profiling, and related methods. If necessary, licking responses and gustatory electrophysiology will be recorded to determine the site of gene action. The goal will be to reduce the list of candidate genes to a number that can be assessed using genetically engineered mice. Finding genes responsible for the consumption of minerals will help us understand why people do not consume satisfactory amounts of them. Low intakes of calcium, magnesium and potassium, and high intakes of sodium, have been linked to the etiology of many diseases affecting the U.S. population, including hypertension, obesity, osteoporosis, and some forms of cancer. The results of the studies proposed here will expose the mechanisms underlying mineral consumption. With this knowledge, it will be possible to target new treatments and strategies that rectify the inadequate intakes and thus ameliorate or eliminate the diseases. PUBLIC HEALTH RELEVANCE: This is a proposal to discover the genetic controls of mineral consumption. Low intakes of calcium, magnesium and potassium, and high intakes of sodium, have been linked to the etiology of many diseases affecting the U.S. population, including hypertension, obesity, osteoporosis, and some forms of cancer. To understand why people do not consume satisfactory amounts of minerals it is fundamental to find the underlying genes responsible for mineral consumption. The information provided by this project will illuminate the basic mechanisms underlying why we choose to consume particular foods and drinks containing minerals. This is important for guiding nutritional interventions and policy. It will also be possible to target new treatments and strategies that rectify the inadequate intakes and thus ameliorate or eliminate the diseases.