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: 7339238
• 负责人: MARIA DE LUCA
• 金额: $ 3.97万
• 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/7339238
• 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

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 age- related 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 trait in natural populations.

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。这 脂肪组织过多的临床问题在于它与许多慢性疾病密切相关，例如 如II型糖尿病、代谢紊乱和冠心病。肥胖的病因很复杂，主要是由于 基因网络的综合效应，以及饮食、年龄、性别和运动的影响。衰老也是一个大问题 贡献者。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疾病状态有关。 以异常细胞因子产生和其他应激诱导分子为特征的炎症。衰老也是 伴随着免疫功能的普遍下降以及伴随的年龄依赖性的免疫功能上调 炎症反应。该项目的假设是进化保守的遗传途径调节年龄 通过利用共同调节，甘油三酯储存和先天免疫功能发生相关变化 分子，并且这些途径可以通过甘油三酯水平和免疫反应的 QTL 分析来识别 在果蝇 melano 中，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，定量遗传方法最有希望 识别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 目的是： 1) 绘制自然遗传变异影响年龄的染色体区域（数量性状位点或 QTL） 黑腹果蝇甘油三酯储存和免疫反应的相关变化。 2) 确定候选基因 影响甘油三酯储存和先天免疫反应的年龄相关变化。候选基因将是 通过使用缺陷的定量互补和精细定位来细化 QTL 的位置来识别 具有先进的交叉线。 3）测试候选者自然序列变异之间的因果关系 甘油三酯储存和先天免疫反应的年龄相关变化的基因和表型变异。要做的事 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 将识别影响甘油三酯储存和免疫反应与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。在 此外，所确定的基因可能是治疗和预防与年龄相关的代谢和疾病的潜在目标。 免疫功能失调。此外，对致病性遗传多态性的性质和频率的了解将导致 更好地了解自然群体中维持这些性状遗传变异的机制。