QTL and QTL Genes Underlying Lactation Performance

描述（由申请人提供）：母乳喂养现在被广泛认为对优化人类的健康、生长和发展以及减轻美国医疗保健的经济负担很重要。美国儿科学会目前的建议是，婴儿应该完全母乳喂养到6个月大。今天，大多数选择母乳喂养的妇女很难维持那么长时间的有效哺乳。过早停止母乳喂养最常见的原因是母乳量不足。生物、生理甚至家族因素可能都在决定泌乳结果中发挥作用。要理解女性之间的这种关键差异，了解调节哺乳的机制是至关重要的。在其他哺乳动物中，如奶牛和老鼠，产奶是一种可遗传的特性。然而，尽管有这些发现，对产奶有贡献的基因在很大程度上是未知的。在牛的29个常染色体上均存在与产奶量有关的数量性状位点（QTL）。这些QTL的基础基因只有少数被鉴定出来。在小鼠中，发表的QTL甚至更少。目前没有一项小鼠QTL研究发表了关于乳发生II、乳成分或乳腺发育期间的产奶量的数据，这些因素对母乳喂养妇女的泌乳成功都很重要。我们的实验室使用产仔交叉饲养方法来测量小鼠的相对产奶量。这些方法可以间接测量周期所有阶段的相对产奶量，其灵敏度和精确度都有所提高，这在以前的研究中是不存在的。我们还测量了乳汁成分、乳腺线粒体功能和母体行为，并在哺乳周期中对乳腺发育和基因表达进行了广泛的分析。这些初步研究表明，乳腺组织氧化代谢暂时与产奶量相关。该提议的假设是，小鼠品系之间产奶量相关性状的表型变异将由乳腺组织氧化代谢的差异来解释，并将与通过计算机关联图谱确定的QTL相关联。我们的交叉培养模式将被用来分离和测量母系在重要的哺乳相关性状的表型差异，这些性状在被称为小鼠多样性小组的自交系小鼠中。然后，我们将确定这些差异是否与乳腺线粒体功能改变有关，然后进行全基因组关联扫描，以确定与这些泌乳性能和线粒体功能性状相关的QTL。这些QTL将被定位到人类Hapmap上，并作为后续RO1的基础，旨在识别决定母乳喂养妇女泌乳表现的基因和基因表达途径。公共卫生相关性：母乳喂养现在被广泛认为对优化人类的健康、生长和发展以及减轻美国卫生保健的经济负担很重要。美国儿科学会目前的建议是，婴儿应该完全母乳喂养到6个月大。今天，大多数选择母乳喂养的妇女很难维持那么长时间的有效哺乳。本提案中描述的实验将使用强大的新小鼠遗传工具来识别和绘制可能调节母乳喂养妇女泌乳结果的基因。

DESCRIPTION (provided by applicant): Breastfeeding is now widely accepted as important to optimizing health, growth and development of humans and reducing the financial burden for health care in the United States. The current recommendation by the American Academy of Pediatrics is that infants be exclusively breast fed to 6 months of age. Today, most women who choose to breast feed have difficulty maintaining a productive lactation for that long. The most common reason cited for early cessation of breastfeeding is insufficient milk volume. Biological, physiological and even familial factors probably all play a role in determining lactation outcome. To understand this critical variability between women, an understanding of the mechanisms regulating lactation is crucial. In other mammals such as the cow and the mouse milk production is a heritable trait. Despite these findings, however, the genes that contribute to milk production are largely unidentified. In the bovine, there are quantitative trait loci (QTL) for milk volume present on all 29 autosomes. Only a few of the genes underlying these QTL have been identified. In the mouse, even fewer QTL have been published. None of the current mouse QTL studies have published data on milk production during lactogenesis II, milk composition, or mammary gland development, factors that are all important to lactational success in breastfeeding women. Our laboratory uses litter-crossfostering approaches to measure relative milk production in the mouse. These approaches have allowed for indirect measurement of relative milk production capacity during all stages of the cycle with a degree of increased sensitivity and precision that has not been present in previous studies. We have also measured milk composition, mammary gland mitochondrial function and maternal behavior, and conducted extensive analysis of mammary gland development and gene expression over the course of the lactation cycle. These preliminary studies demonstrate that mammary tissue oxidative metabolism is temporally linked to milk production The hypothesis of this proposal is that phenotypic variation in milk production-associated traits among mouse strains will be accounted for by differences in mammary tissue oxidative metabolism and will be linked to QTL identified through in-silico association mapping. Our cross-fostering paradigm will be used to isolate and measure maternal phenotypic differences in important lactation-related traits among a collection of inbred mouse strains known as the mouse diversity panel. We will then determined if these differences are associated with altered mammary mitochondrial function and then conduct In-silico whole genome association scans to identify the QTL linked to these lactation performance and mitochondrial function traits. These QTL will be mapped onto the human Hapmap and serve as the basis for a subsequent RO1 aimed at identifying genes and gene-expression pathways which determine lactation performance in breastfeeding women. PUBLIC HEALTH RELEVANCE: Breastfeeding is now widely accepted as important to optimizing health, growth and development of humans and reducing the financial burden for health care on the United States. The current recommendation by the American Academy of Pediatrics is that infants be exclusively breast fed to 6 months of age. Today, most women who choose to breast feed have difficulty maintaining a productive lactation for that long. The experiments described in this proposal will use powerful new mouse genetic tools to identify and map the genes which could regulate lactation outcomes in breastfeeding women.