QTL mapping age-related changes in lipid storage

描述（由申请人提供）： 肥胖，定义为身体脂肪或脂肪组织过量，是一种对人类健康产生不利影响的疾病。过量脂肪组织的临床问题在于其与许多慢性疾病如II型糖尿病、代谢紊乱和冠心病的强烈关联。肥胖的病因复杂，是基因网络的综合作用，以及饮食、年龄、性别和运动的影响。老龄化也是一个主要因素。脂肪量的普遍增加通常发生在生命的第三和第七个十年之间。有趣的是，肥胖和相关的代谢疾病已被证明与慢性炎症状态相关，其特征在于异常的细胞因子产生和其他应激诱导的分子。衰老还伴随着免疫功能的普遍下降和伴随的炎症反应的年龄依赖性上调。本项目的假设是，进化上保守的遗传途径通过利用共同的调节分子来调节与年龄相关的甘油三酯储存和先天免疫功能的变化，并且这些途径可以通过对黑果果蝇（Drosophila melano，qaster）甘油三酯水平和免疫应答的QTL分析来鉴定。甘油三酯储存和免疫应答都是复杂的多基因性状，依赖于大量基因的相互作用。因此，数量遗传学的方法提供了最有前途的多效性基因座，有助于这些性状的年龄相关的变化。该项目的具体目标是：1）地图的染色体区域（数量性状位点或QTL），在自然遗传变异影响年龄相关的变化，甘油三酯储存和免疫反应的黑腹果蝇。2)识别影响甘油三酯储存和先天免疫应答中年龄相关变化的候选基因。候选基因将通过使用对缺陷的定量互补和用先进的互交系进行精细作图来细化QTL的位置来鉴定。3)测试候选基因中的自然序列变异与甘油三酯储存和先天免疫应答中年龄相关变化的表型变异之间的因果关系。为此，我们将使用随机交配群体中等位基因样本的连锁不平衡作图。本研究将确定影响甘油三酯储存和免疫反应的年龄相关变化的基因和遗传网络，并阐明这些性状受多效性基因座调控的程度。这些基因的鉴定将可能为人类肥胖提供新的模型，并可作为年龄特异性风险评估的遗传标记。此外，所鉴定的基因可能是治疗和预防与年龄相关的代谢和免疫功能障碍的潜在靶点。此外，知识的性质和频率的致病性遗传多态性将导致更好地理解的机制，保持这些性状的遗传变异在自然种群。

DESCRIPTION (provided by applicant): Obesity, defined as an excess of body fat or adipose tissue, is a condition that adversely affects human health. The clinical problem of excessive adipose tissue resides in its strong association with a number of chronic diseases such as type II diabetes, metabolic disorders and coronary heart disease. The etiology of obesity is complex, resulting from the combined effect of a network of genes, and the influences of diet, age, gender and exercise. Aging is also a major contributor. A general increase in fat mass typically occurs between the third and seventh decades of life. Interestingly, obesity and related metabolic diseases have been shown to be associated with a state of chronic inflammation characterized by abnormal cytokine production and other stress-induced molecules. Aging is also accompanied by a general decline in immune function and a concomitant age-dependent up-regulation of the inflammatory response. The hypothesis of this project is that evolutionary conserved .qenetic pathways regulate age related changes in triglyceride storage and innate immune function through the utilization of common regulatory molecules, and that these pathways can be identified by QTL analyses of triglyceride levels and immune responses in Drosophila melano,qaster. Both triglyceride storage and immune response are complex polygenic traits, relying on the interaction of a large number of genes. Therefore, a quantitative genetic approach offers the most promise for identifying pleiotropic loci that contribute to the age-related changes in these traits. The specific aims of this project are to: 1) Map chromosomal regions (quantitative trait loci or QTL) at which natural genetic variation affects agerelated changes in triglyceride storage and immune response of D.melanogaster. 2) Identify candidate genes affecting age-related changes in both triglyceride storage and innate immune response. Candidate genes will be identified by refining the position of QTL using quantitative complementation to deficiencies and fine-scaled mapping with advanced intercross lines. 3) Test the causal relationship between natural sequence variation in candidate genes and phenotypic variation in age-related changes in triglyceride storage and innate immune response. To do this, we will use linkage disequilibrium mapping of a sample of alleles from a randomly mating population. This study will identify genes and genetic networks affecting age related changes in triglyceride storage and immune response and elucidate the extent to which these traits are regulated by pleiotropic loci. Identification of these genes will likely provide new models for human obesity and could serve as genetic markers for age-specific risk assessment. In addition, the genes identified could be potential targets for the treatment and prevention of age-related metabolic and immune dysfunction. Moreover, knowledge of the nature and frequency of causative genetic polymorphisms will lead to a better understanding of the mechanisms that maintain genetic variation in these traits in natural populations.