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

 描述(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，饮食等环境因素导致了这些疾病，也是基因造成的。因此，经常建议改变饮食以缓解代谢紊乱2-4。然而，目前还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表现出不同的代谢表型，一般为5-10。在这些个体之间环境因素保持不变的情况下，必须对基因调控负责。尽管许多研究已经对饮食如何调节影响寿命、衰老和健康的分子反应提供了实质性的见解11-20，但很少有研究考虑自然发生的遗传变异的影响。了解基因变异如何影响饮食反应，对于为肥胖相关的健康风险提供个性化治疗至关重要。我建议确定影响饮食相关长寿和健康的变异，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，它允许在完全饮食干预和促进遗传操作的情况下进行全长寿命分析。Kapahi实验室和其他人已经证明，限制蛋白质摄入而不营养不良会导致代谢转变，从而导致寿命延长21-23岁。尽管TOR和胰岛素样信号转导等因素被认为是代谢适应的关键24-25，但它们对个体的影响程度差异很大，毫无疑问，还有其他关键的代谢、神经和营养吸收途径来调节这些表型。众所周知，遗传变异会影响对饮食的反应，但其中特定的基因或变异还没有确定26-30。果蝇是识别这些遗传成分的最佳模型，特别是因为最近发展了一组全序列纯合野生蝇系，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)确定调节特定营养物质体能和健康的遗传和表型成分；3)验证已确定的遗传变异，并揭示它们如何影响代谢途径。考虑到肥胖症和相关疾病在世界范围内日益普遍，特别是在美国32-34，有必要确定使个人易患疾病的遗传成分和对营养的具体反应。通过剖析影响这些情况的因素并确定由此产生的影响途径，将有可能确定特定的药物靶点，以便根据不同的代谢情况进行个体化关注和治疗护理。这些疗法与饮食干预相结合，将有助于最大限度地努力增加健康和寿命。

 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.