Genetic controls of mineral consumption

描述（由申请人提供）：这是一个发现对钙、镁、钾和钠的消耗负责的基因控制的项目。我们已经确定了几个与这些矿物质消耗相关的数量性状位点（qtl）。我们在此建议鉴定其中一些qtl的潜在基因。要做到这一点，我们将首先生产同源菌株的小鼠渗入含有QTL染色体片段。这将使用经典的基因型选择方法或利用最近开发的经济菌株来完成。作为经典方法的一个例子，我们建议完全生产同源小鼠系，分离Chr 17上的QTL，该QTL在CaCl2偏好（LOD = 45）和糖精偏好（LOD = 100）方面具有令人印象深刻的高LOD分数。作为经济起源方法的一个例子，我们建议建立同源系来分离Chr 5上的QTL，其NaCl偏好的LOD评分为8.5。据我们所知，这将是第一个表征钠消耗的QTL。一旦同源菌株建立，我们将评估居住在同源区间的候选基因。这将使用计算机分析、基因表达谱和相关方法的组合来完成。如有必要，将记录舔舐反应和味觉电生理，以确定基因作用的位置。目标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。找到与矿物质消耗有关的基因将有助于我们理解为什么人们不能摄入足够的矿物质。钙、镁和钾的低摄入量和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、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耗的机制。有了这些知识，就有可能针对新的治疗方法和战略，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.