ENDOCANNABINOID BIOMARKERS OF OBESITY USING INTEGRATED GENOMICS AND METABOLOMICS

使用综合基因组学和代谢组学研究肥胖的内源性大麻素生物标志物

基本信息

批准号：
7437241
负责人：
JACK C SIPE
金额：
$ 18.57万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2009-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7437241
关键词：
2-arachidonylglycerol Addictive Behavior Address Affect American Amides Applications Grants Area Automobile Driving Basic Science Behavior Binding Biological Markers Blood Blood Circulation Body Weight Body fat Body measure procedure CNR1 gene Candidate Disease Gene Cannabinoids Cannabis Cardiovascular Diseases Central obesity Chemicals Clinic Clinical Collaborations Complex Consent DNA Databases Deposition Development Diagnostic Diagnostic tests Disease Drug Addiction Drug abuse Eating Endocannabinoids Enrollment Environmental Risk Factor Enzymes Epidemic Equipment and supply inventories Ethnic Origin Family member Fatty Acids Fatty acid glycerol esters Food Intake Regulation Fresh Frozen Plasmas Future GTP-Binding Proteins Gene Abnormality Gene Mutation Genes Genetic Genetic Variation Genomics Goals Health High Prevalence Human Individual Intestines Laboratories Laboratory Research Ligands Lipids Measures Metabolic syndrome Methods Missense Mutation Molecular Molecular Genetics Monoacylglycerol Lipases Mutation Mutation Detection Non-Insulin-Dependent Diabetes Mellitus Obesity Other Finding Overweight Pathway interactions Patients Peripheral Phase Phenotype Plasma Play Population Prevalence Probability Public Health Publications Publishing Rate Research Research Personnel Research Project Grants Rewards Risk Risk Assessment Risk Factors Role Sampling Screening procedure Signal Transduction Signaling Molecule Source Staging System Techniques Testing Thinking Variant Weight Weight maintenance regimen Work anandamide base cardiovascular risk factor case control clinically relevant craving design fatty acid amide hydrolase feeding gene discovery human study improved lipid metabolism metabolomics novel obesity treatment research and development research study response rimonabant

项目摘要

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.

描述（由申请人提供）：该CEBRA赠款的主要目标是利用一种新型的综合基因组学和代谢组学方法来开发超重疾病的生物标志物临床相关且易于获得的内源性内源性内源性疾病，以改善受影响个人的基于ECS疾病的疾病疗法的风险评估和选择。该项目与公共卫生直接相关，因为超重（OW）和肥胖症（OB）被认为是二十一世纪最严重，最普遍，全球公共卫生问题最严重，最昂贵的全球公共卫生问题之一。尽管人们认为原因，危险因素和并发症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为在食物摄入和脂肪代谢的调节中起主要作用，因此在OW和OB的发展中起着作用。目的是识别和验证循环的ECS生物标志物，其中包括内源性大麻素中的遗传突变，与脂肪酸酰胺活性脂质的脂肪酸酰胺活性脂质的代谢分析中，与病例对照组相比，脂肪酸酰胺生物活性脂质的代谢分析升高。遗传和代谢组生物标志物发现的整合将使ECS风险概况发展用于诊断评估，疾病分期和对内源性大麻素拮抗剂疗法（如Rimonabant（Acomplia））的反应。该项目通过开发可从基础研究到诊所使用的循环内源性大麻素生物标志物来解决迫切的需求。我们的工作假设是，具有遗传学降低的FAAH或MAGL活性以及内源性大麻素张力水平的受试者特别适合降低体重的影响。由于肥胖症被认为是具有异常奖励和渴望反应的一种成瘾行为的一种表现，因此通过该CEBRA开发的内源性大麻素生物标志物不仅与扩大的肥胖症流行直接相关，而且可能与药物成瘾行为相关。该项目将显着加速未来的肥胖研究，并将由于这些内源性大麻素生物标志物的临床和研究使用增加而支持更新颖的基于ECS的治疗方案，以期在全球范围内超重和肥胖。这个尖端的基础研究项目旨在找到这些疾病患者血液中超重和肥胖的新标记。我们将在患者中测量人体自身循环的大麻样化学物质，并发现具有超重和肥胖风险的基因异常。我们的发现将通过帮助人们选择肥胖问题的最佳治疗方法，发现其他有肥胖风险的家庭成员以及发现可能通过更多的实验室研究产生新的肥胖症治疗的危险因素来改善公共卫生。