Identifying the pathways by which naturally-occurring genetic variants associated with nutrient response regulate longevity and health.

确定与营养反应相关的自然发生的遗传变异调节寿命和健康的途径。

• 批准号: 9052069
• 负责人: Kenneth Anthony Wilson
• 金额: $ 2.71万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052069
• 关键词: Affect; Age; Aging; Animal Model; Attention; Body Weight; Caring; Cessation of life; Data; Development; Diet; Diet Modification; Dietary Intervention; Dietary intake; Disease; Drosophila genus; Drosophila melanogaster; Drug Targeting; Environmental Risk Factor; Genes; Genetic; Genetic Variation; Genotype; Health; Human; Individual; Insulin; Investigation; Length; Life; Longevity; Malnutrition; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Molecular; Neurologic; Nutrient; Nutritional; Obesity; Pathway interactions; Patient Self-Report; Phenotype; Physiological; Play; Prevalence; Proteins; Regulation; Resistance; Risk; Role; Signal Transduction; Site-Directed Mutagenesis; Speed; Starvation; System; Therapeutic; Translating; Triglycerides; Variant; Walking; Work; biological adaptation to stress; case-by-case basis; disorder prevention; fly; genetic association; genetic manipulation; genetic resource; genetic variant; genome wide association study; improved; insight; lipid metabolism; mortality; nutrient absorption; personalized medicine; physical conditioning; prevent; protein intake; public health relevance; reproductive; research study; response; trait

 DESCRIPTION (provided by applicant): Obesity-related disorders are associated with poor health and decreased lifespan in humans1. It is well understood that environmental factors such as diet contribute to these disorders as well as genotype. As such, dietary alterations are frequently suggested to ease metabolic dysfunction2-4. It is not understood, however, why different individuals display variable phenotypic results after dietary intervention. Furthermore, t is not known why different individuals who consume the same diet show different metabolic phenotypes in general5- 10. With environmental factors remaining constant between these individuals, genetic regulation must be responsible. Although many studies have provided substantial insight into how diet can regulate molecular responses affecting longevity, aging, and health11-20, few studies take into consideration the effects of naturally- occurring genetic variation. Understanding how genetic variation affects dietary response is crucial to providing personalized treatment for obesity-related health risks. I propose to identify the variants that influence diet- related longevity and health and determine the mechanisms by which these variants regulate response. I will reveal these variants and pathways using Drosophila melanogaster as a model organism, which allows for full- length lifespan analysis with complete dietary intervention and facilitated genetic manipulations. It has been shown by the Kapahi lab and others that restricting protein intake without malnutrition induces metabolic shifts that can result in lifespan extension21-23. Although factors such as TOR and insulin-like signaling have been implicated as key to metabolic adaptations24-25, the degree to which they affect individuals varies greatly and there are undoubtedly other key metabolic, neurological, and nutrient absorption pathways regulating these phenotypes. It is known that genetic variation can affect response to diet, but specific genes or variants within them are yet to be identified26-30. Drosophila is the optimal model for identifying these genetic components, especially due to the recent development of a panel of fully-sequenced homozygous wild fly lines which is especially useful in genome-wide association studies31. I propose to undertake the following three aims: 1) Determine the genetic variants and physiological traits that influence longevity and mortality; 2) Identify genetic and phenotypic components that regulate nutrient-specific physical capability and health; and 3) Validate the genetic variants identified and reveal how they influence metabolic pathways. Considering the increasing prevalence of obesity and related disorders world-wide, particularly in the United States32-34, it is essential to determine the genetic components that predispose individuals towards disease and specific responses to nutrients. By dissecting the factors that influence these conditions and determining the resulting affected pathways, it will become possible to identify specific drug targets to allow for individualized attention and therapeutic care on a case-by-case basis for differing metabolic conditions. Together, these therapeutics combined with dietary interventions will help maximize efforts to increase health and lifespan.

 描述（由申请人提供）：肥胖相关疾病与人类健康状况不佳和寿命缩短有关1。众所周知，饮食等环境因素以及基因型都会导致这些疾病。因此，经常建议改变饮食来缓解代谢功能障碍2-4。然而，尚不清楚为什么不同的个体在饮食干预后表现出不同的表型结果。此外，尚不清楚为什么食用相同饮食的不同个体通常会表现出不同的代谢表型5-10。由于这些个体之间的环境因素保持不变，因此遗传调控必须负责。尽管许多研究对饮食如何调节影响寿命、衰老和健康的分子反应提供了深入的见解11-20，但很少有研究考虑到自然发生的遗传变异的影响。了解遗传变异如何影响饮食反应对于为肥胖相关健康风险提供个性化治疗至关重要。我建议找出影响饮食相关寿命和健康的变异，并确定这些变异调节反应的机制。我将使用黑腹果蝇作为模式生物来揭示这些变异和途径，这允许通过完整的饮食干预和便利的基因操作进行全长寿命分析。 Kapahi 实验室和其他实验室已经证明，限制蛋白质摄入而不导致营养不良会引起代谢变化，从而延长寿命21-23。尽管 TOR 和类胰岛素信号传导等因素被认为是代谢适应的关键24-25，但它们影响个体的程度差异很大，并且毫无疑问还有其他关键的代谢、神经和营养吸收途径调节这些表型。众所周知，遗传变异会影响对饮食的反应，但其中的特定基因或变异尚未确定26-30。果蝇是识别这些遗传成分的最佳模型，特别是由于最近开发了一组完全测序的纯合野生蝇系，这在全基因组关联研究中特别有用31。我建议实现以下三个目标：1）确定影响寿命和死亡率的遗传变异和生理特征； 2) 识别调节特定营养素身体能力和健康的遗传和表型成分； 3) 验证已识别的遗传变异并揭示它们如何影响代谢途径。考虑到肥胖和相关疾病在世界范围内日益流行，特别是在美国32-34，有必要确定使个体易患疾病的遗传成分和对营养素的特定反应。通过剖析影响这些状况的因素并确定由此产生的受影响途径，将有可能确定特定的药物靶点，以便针对不同的代谢状况根据具体情况进行个性化关注和治疗护理。这些疗法与饮食干预相结合将有助于最大限度地提高健康和寿命。