QTL mapping age-related changes in lipid storage

QTL 绘制脂质储存中与年龄相关的变化

• 批准号: 6876766
• 负责人: MARIA DE LUCA
• 金额: $ 32.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876766
• 关键词: Drosophilidae; aging; alleles; arthropod genetics; gene complementation; gene mutation; genetic markers; genotype; immune response; immunogenetics; immunoregulation; linkage disequilibriums; linkage mapping; lipid metabolism; obesity; phenotype; quantitative trait loci; single nucleotide polymorphism; triglycerides

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.

描述（由申请人提供）： 肥胖症定义为过量的体内脂肪或脂肪组织，是对人类健康的不利影响。过度脂肪组织的临床问题与多种慢性疾病（例如II型糖尿病，代谢性疾病和冠心病）有很强的联系。肥胖症的病因很复杂，这是由于基因网络的综合作用以及饮食，年龄，性别和运动的影响。衰老也是主要贡献者。脂肪质量的普遍增加通常发生在生命的第三十年到第七十年之间。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有关，其特征是异常的细胞因子产生和其他胁迫诱导的分子。衰老还伴随着免疫功能的普遍下降，炎症反应的年龄依赖性上调。该项目的假设是，进化保守的途径通过利用共同的调节分子来调节甘油三酸酯储存和先天免疫功能的年龄相关的变化，并且可以通过甘油三酸酯水平的QTL分析来鉴定这些途径，甘油酸酯水平和免疫反应在果蝇中，Qaster，qaster，qaster。甘油三酸酯的储存和免疫反应都是复杂的多基因性状，依赖于大量基因的相互作用。因此，一种定量遗传方法为识别多效基因座提供了最有前途的，这有助于这些特征与年龄相关的变化。该项目的具体目的是：1）自然遗传变异会影响甘油三酸酯储存的变化和D.Melanogaster的免疫反应的染色体区域（定量性状基因座或QTL）。 2）确定影响年龄相关的甘油三酸酯储存和先天免疫反应变化的候选基因。候选基因将通过使用对缺陷的定量互补和与高级间交叉线的精细尺度映射来完善QTL的位置来识别候选基因。 3）测试候选基因的自然序列变化与年龄相关的甘油三酸酯储存和先天免疫反应变化的表型变化之间的因果关系。为此，我们将使用从随机交配种群中的等位基因样本进行连锁不平衡映射。这项研究将确定影响甘油三酸酯储存和免疫反应中与年龄相关的变化的基因和遗传网络，并阐明这些特征受到多效性基因座调节的程度。这些基因的鉴定可能会为人类肥胖提供新的模型，并可以作为特定年龄风险评估的遗传标记。此外，确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标。此外，对病变遗传多态性的性质和频率的了解将使人们更好地理解自然种群中这些特征中遗传变异的机制。