ENDOCANNABINOID BIOMARKERS OF OBESITY USING INTEGRATED GENOMICS AND METABOLOMICS

描述（由申请人提供）：这项CEBRA资助的主要目标是利用一种新的整合基因组学和代谢组学方法来开发临床相关且易于获得的超重疾病内源性大麻素系统（ECS）生物标志物，以改善患病个体的风险评估和基于ECS的疾病修饰疗法的选择。该项目与公共卫生直接相关，因为超重和肥胖被认为是21世纪最严重、最普遍和最昂贵的全球公共卫生问题之一。虽然病因、危险因素和并发症被认为涉及许多复杂的遗传和环境因素，但内源性大麻素系统最近被确定在调节食物摄入和脂肪代谢方面起着重要作用，因此，目的是鉴定和验证循环ECS生物标志物，包括主要内源性大麻素失活酶（FAAH和MAGL）的基因突变，以及与病例对照人群相比，OW和OB受试者循环中脂肪酸酰胺生物活性脂质的代谢组学分析。整合遗传和代谢组学生物标志物的发现将有助于开发ECS风险概况，用于诊断评估、疾病分期和对内源性大麻素拮抗剂治疗（如利莫那班）的反应可能性。本项目通过开发循环内源性大麻素生物标志物，解决了从基础研究到临床应用的迫切需求。我们的工作假设是，FAAH或MAGL活性基因降低和内源性大麻素水平升高的受试者特别容易受到利莫那班的减肥效果的影响。由于肥胖疾病被认为是一种具有异常奖励和渴望反应的成瘾行为的表现，因此通过CEBRA开发的内源性大麻素生物标志物不仅与不断扩大的肥胖流行病直接相关，而且可能与药物成瘾行为有关。随着这些内源性大麻素生物标志物在全球范围内用于超重和肥胖的临床和研究，该项目将显著加速未来的肥胖研究，并将支持开发更多基于ecs的新型治疗方案。这个前沿的基础研究项目旨在从患有这些疾病的人的血液中找到超重和肥胖的新标记。我们将测量患者体内循环的类似大麻的化学物质，发现可能导致超重和肥胖的基因异常。我们的研究结果将用于改善公众健康，帮助人们选择最好的肥胖治疗方法，发现其他有肥胖风险的家庭成员，并通过更多的实验室研究发现可能产生新的肥胖治疗方法的风险因素。

DESCRIPTION (provided by applicant): The primary goal of this CEBRA grant is to utilize a novel integrated genomics and metabolomics approach to develop clinically relevant and readily available endocannabinoid system (ECS) biomarkers of overweight disorders that will improve risk assessment and selection of ECS-based disease modifying therapies for affected individuals. This project is directly related to public health because overweight (OW) and obesity (OB) are considered to be one of the most serious, pervasive and costly global public health problems of the twenty-first century. Although the causes, risk factors and complications are thought to involve many complex genetic and environmental factors, the endocannabinoid system has recently been identified as playing a major role in the regulation of food intake and fat metabolism and, consequently, in the development of OW and OB. The objective is to identify and validate circulating ECS biomarkers that include genetic mutations in the main endocannabinoid inactivating enzymes (FAAH and MAGL) and metabolomic profiling of fatty acid amide bioactive lipids that are elevated in the circulation of OW and OB subjects compared to case control populations. Integration of the genetic and metabolomic biomarker findings will enable the development of an ECS risk profile for use in diagnostic assessments, disease staging and likelihood of response to endocannabinoid antagonist therapies such as Rimonabant (Acomplia). This project addresses an urgent need by developing circulating endocannabinoid biomarkers that may be used from basic research to the clinic. Our working hypothesis is that subjects with genetically reduced FAAH or MAGL activity and heightened levels of endocannabinoid tone would be particularly amenable to the weight-lowering effects of Rimonabant. Since obesity disorders are thought to be a manifestation of a type of addictive behavior with abnormal reward and craving responses, the endocannabinoid biomarkers developed through this CEBRA will be directly relevant not only to the expanding obesity epidemic but may also be relevant to drug addiction behaviors. This project will significantly accelerate future obesity research and will support the development of more novel ECS-based treatment options as a result of increased clinical and investigational use of these endocannabinoid biomarkers for overweight and obesity worldwide. This cutting edge basic research project is designed to find new markers of overweight and obesity in the blood of people with these disorders. We will measure the body's own circulating Cannabis-like chemicals in patients and find gene abnormalities that are risks for overweight and obesity. Our findings will be used to improve public health by helping people with the choice of the best treatment for their obesity problems, find other family members at risk of becoming obese and by the discovery of risk factors that could produce new obesity treatments through more laboratory research.