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: 7276091
• 负责人: MARIA DE LUCA
• 金额: $ 34.14万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276091
• 关键词: Adipose tissue; Affect; Age; Aging; Alleles; Biological Models; Body fat; Candidate Disease Gene; Chromosome Mapping; Chronic; Chronic Disease; Clinical; Complex; Condition; Coronary heart disease; Diabetes Mellitus; Diet; Drosophila genus; Drosophila melanogaster; Etiology; Exercise; Fatty acid glycerol esters; Frequencies; Gender; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Goals; Health; Human; Immune; Immune System Diseases; Immune response; Immune system; Inflammation; Inflammatory Response; Knowledge; Lead; Life; Linkage Disequilibrium Mapping; Lipids; Lipodystrophy; Mammals; Maps; Metabolic; Metabolic Diseases; Modeling; Nature; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Organism; Partner in relationship; Pathway interactions; Polygenic Traits; Population; Positioning Attribute; Prevention; Procedures; Production; Quantitative Genetics; Quantitative Trait Loci; Regulation; Research; Research Proposals; Resources; Risk Assessment; Sampling; Stress; Testing; Transcriptional Activation; Triglycerides; Up-Regulation; Variant; age related; cytokine; immune function; lipid biosynthesis; trait

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）： 肥胖被定义为体内脂肪或脂肪组织过多，是一种对人类健康产生不利影响的疾病。脂肪组织过多的临床问题在于其与许多慢性疾病如II型糖尿病、代谢紊乱和冠心病密切相关。肥胖的病因很复杂，是基因网络的综合作用以及饮食、年龄、性别和运动的影响的结果。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个和第七个十年之间。有趣的是，肥胖和相关代谢疾病已被证明与慢性炎症状态有关，其特征是细胞因子产生异常和其他应激诱导分子。衰老还伴随着免疫功能的普遍下降以及随之而来的年龄依赖性炎症反应的上调。该项目的假设是，进化保守的遗传途径通过利用常见的调节分子来调节甘油三酯储存和先天免疫功能的年龄相关变化，并且这些途径可以通过黑腹果蝇中甘油三酯水平和免疫反应的 QTL 分析来识别，qaster。甘油三酯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，定量遗传方法最有可能识别出导致这些性状与年龄相关的变化的多效性基因座。该项目的具体目标是： 1) 绘制染色体区域（数量性状位点或 QTL），在该区域自然遗传变异会影响黑腹果蝇甘油三酯储存和免疫反应的年龄相关变化。 2) 确定影响甘油三酯储存和先天免疫反应中与年龄相关的变化的候选基因。候选基因将通过使用缺陷的定量互补和先进的杂交系的精细定位来细化 QTL 的位置来鉴定。 3) 测试候选基因的自然序列变异与甘油三酯储存和先天免疫反应的年龄相关变化的表型变异之间的因果关系。为此，我们将使用来自随机交配群体的等位基因样本的连锁不平衡作图。这项研究将鉴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节的程度。这些基因的鉴定可能会为人类肥胖提供新模型，并可作为特定年龄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目标。此外，了解致病性遗传多态性的性质和频率将有助于更好地理解自然群体中这些性状的遗传变异维持机制。