Drug Abuse Related Polymorphism in Fatty Acid Amide Hydrolase

脂肪酸酰胺水解酶与药物滥用相关的多态性

• 批准号: 7230317
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 18.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230317
• 关键词: Address; Adenine; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Americas; Amides; Amino Acids; Animals; Behavior; Biochemical; Biological Models; Blood; Brain; COS Cells; Cannabinoids; Chemicals; Chronic; Cytosine; Data; Diabetes Mellitus; Disruption; Drug abuse; Eating; Endocannabinoids; Engineering; Enzymatic Biochemistry; Enzymes; Etiology; Evolution; Exhibits; Exons; Exposure to; Fatty Acids; Food; Future; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Half-Life; Health; Human; Hydrolase Gene; In Vitro; Individual; Institutes; Intake; Intervention; Knock-in Mouse; Lead; Life; Link; Liquid substance; Locomotion; Malignant Neoplasms; Metabolic; Metabolism; Methods; Modeling; Mus; Mutate; Mutation; Neurologic; Nociception; Obesity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Process; Proline; Proteins; Public Health; Recombinants; Research; Research Personnel; Rewards; Risk; Sampling; Self Administration; Series; Single Nucleotide Polymorphism; Sleep; Societies; System; Testing; Therapeutic; Threonine; Tissues; Variant; Work; addiction; analytical method; behavior test; cohort; cost; day; dosage; drug seeking behavior; fatty acid amide hydrolase; feeding; human population study; human study; in vivo Model; inhibitor/antagonist; insight; mouse model; mutant; mutation carrier; novel; programs

DESCRIPTION (provided by applicant): A single nucleotide polymorphism has been correlated with human populations at increased risk for drug and alcohol abuse. Affected individuals carry a variant form of fatty acid amide hydrolase, an enzyme responsible for setting cannabinoid tone in the brain. Biochemical data on this point mutant have revealed no significant deviations from its wild-type counterpart. However, fluids samples from affected individuals have revealed that carriers of this mutation express levels of this enzyme at roughly half that of wild-type cohorts. Could this observation provide an explanation for the observed drug abuse behaviors, or does this mutation manifest its effects in unpredicted ways? The only clear way to address these questions is to create a living model system. This proposal seeks to create a mouse harboring the same mutation found in the human population studies. Once this "knock-in" mouse is engineered, a series of behavioral tests will be used to determine if the animals replicate the drug abuse behaviors correlated in humans. Further, possible mechanisms to explain these behaviors will be sought. These mechanisms include the possible alteration of endogenous cannabinoid tone and/or the selective dysregulation of individual fatty acid amide metabolites. If this mouse model is found to exhibit increased susceptibility to drug abuse behaviors, it will provide a very powerful platform for future research into the evolution of these behaviors and possible means of pharmacological intervention. The National Institute on Drug Abuse has called drug abuse and addiction "one of America's most challenging public health problems", rivaling both diabetes and cancer in terms of costs to society. Identifying genetic contributions to drug abuse behaviors can provide powerful insights into etiology and may one day offer personalized treatment options for those at risk for these health concerns.

描述（由申请人提供）：单核苷酸多态性与药物和酒精滥用风险增加的人群相关。受影响的个体携带一种变体形式的脂肪酸酰胺水解酶，这种酶负责在大脑中设置大麻素的音调。该点突变体的生化数据显示其与野生型没有显著差异。然而，来自受影响个体的液体样本显示，这种突变的携带者表达这种酶的水平大约是野生型队列的一半。这一观察结果能否为观察到的药物滥用行为提供解释，或者这种突变是否以不可预测的方式表现出其影响？解决这些问题的唯一明确方法是创建一个活的模型系统。这一提议旨在创造一种携带与人类种群研究中发现的相同突变的小鼠。一旦这种“敲入”老鼠被设计出来，一系列的行为测试将被用来确定这些动物是否会复制与人类滥用药物相关的行为。此外，将寻求解释这些行为的可能机制。这些机制包括内源性大麻素张力的可能改变和/或单个脂肪酸酰胺代谢物的选择性失调。如果发现该小鼠模型对药物滥用行为的易感性增加，将为未来研究这些行为的演变和可能的药物干预手段提供一个非常强大的平台。国家药物滥用研究所称药物滥用和成瘾是“美国最具挑战性的公共卫生问题之一”，就社会成本而言，与糖尿病和癌症相媲美。确定药物滥用行为的遗传因素可以提供对病因的有力见解，并可能有一天为那些有这些健康问题风险的人提供个性化的治疗选择。