Genetic controls of mineral consumption

描述(申请人提供)：这是一个发现导致钙、镁、钾和钠消耗的基因控制的项目。我们已经确定了几个与这些矿物质消耗相关的数量性状基因座(QTL)。我们建议在这里确定其中一些QTL的潜在基因。为了做到这一点，我们将首先培育出含有QTL的染色体片段导入的同源小鼠品系。这将使用经典的按基因选择的方法或通过利用最近开发的共生体品系来完成。作为经典方法的一个例子，我们建议完成同源小鼠品系的生产，分离出Chr 17上的一个QTL，该QTL对CaCl2偏好(LOD=45)和糖精偏好(LOD=100)具有令人印象深刻的高LOD分数。作为共体起源方法的一个例子，我们建议创造同源系来分离Chr5上的一个QTL，其盐偏好的LOD分数为8.5。据我们所知，这将是第一个表征钠消费的QTL。一旦建立了同源菌株，我们将评估驻留在同源区间的候选基因。这将使用计算机分析、基因表达谱分析和相关方法相结合来完成。如有必要，将记录舔食反应和味觉电生理学，以确定基因作用的位置。目标将是将候选基因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、镁和钾的摄入量低，钠的摄入量高，与许多影响美国人口的疾病的病因有关，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背后的机制。有了这些知识，就有可能针对新的治疗方法和策略，纠正摄入不足的情况，从而改善或消除这些疾病。

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.