FAAH GENE MUTATIONS: RISK FACTORS IN DRUG USE/ADDICTION

描述（由申请人提供）：吸毒成瘾给个人、家庭和文明社会造成了巨大的损失。这项基础研究计划响应PA #00-115，通过鉴定、表征和生化测试脂肪酸酰胺水解酶（FAAH）的遗传变异来解决药物滥用和成瘾问题，FAAH是内源性大麻素水平和大脑内源性大麻素系统（ECS）张力的主要分解代谢调节因子，可能导致这种遗传复杂疾病的脆弱性。脑ECS是最近发现的一种进化的古老逆行信号通路，具有持续调节（下调）许多关键神经系统中的神经递质释放的能力，包括中脑边缘多巴胺成瘾/奖励系统。人们早就知道，在一些脆弱的个体中，大麻的使用可能与药物滥用和成瘾有关，动物研究表明大麻素在成瘾中起作用。由于脑内源性大麻素与外源性大麻素具有相同的受体靶点和活性，因此该建议的中心假设是FAAH的功能异常遗传变异可能导致药物滥用和成瘾的脆弱性风险。本提案的长期目标和目的是在具有特定类型药物滥用的匿名受试者中识别和生化测试重要的FAAH突变，并将这些突变作为易受药物滥用或依赖的风险因素联系起来。本提案的重点是在人类FAAH基因的初步研究中发现的基因突变。该研究计划从遗传学、生物化学和功能上对人类FAAH突变进行评估，并在来自特定药物成瘾者的大量匿名DNA样本中确认特定突变蛋白的风险，这些样本按年龄、性别、种族/民族分层，与匹配的对照组进行比较。总的来说，这些实验目的旨在验证自然发生的FAAH遗传变异作为药物滥用和依赖易感性的预测因素，以便及早发现风险最大的个体，并测试针对这一重大公共卫生问题的治疗策略。

DESCRIPTION (provided by applicant): Drug addiction exacts a heavy toll on the affected individuals, their families and civilized society. This basic research proposal in response to PA #00-115 approaches the problem of drug abuse and addiction by identifying, characterizing and biochemically testing genetic variants in fatty acid amide hydrolase (FAAH), the principal catabolic regulator of endocannabinoid levels and the brain endogenous cannabinoid system (ECS) tone that may contribute to vulnerability in this genetically complex disorder. The brain ECS is a recently discovered but evolutionary ancient retrograde signaling pathway with the capacity to continuously modulate (downregulate) neurotransmitter release in many critical neuronal systems, including the mesolimbic dopamine addiction/reward system. It has long been known that cannabis use may be associated with drug abuse and addiction in some vulnerable individuals and animal studies indicate that cannabinoids play a role in addiction. Because brain endogenous cannabinoids have the same receptor targets and activity as exogenous cannabis, the central hypothesis of this proposal is that functionally abnormal genetic variants of FAAH may contribute to the risk of vulnerability for drug abuse and addiction. The long term objectives and aims of this proposal are to identify and biochemically test significant FAAH mutations in anonymous subjects with specific types of drug abuse and to link these mutations as risk factors for vulnerability to drug abuse or dependence. This proposal focuses on genetic mutations identified in preliminary studies of the human FAAH gene. The plan is to genetically, biochemically and functionally evaluate significant human FAAH mutations and to confirm the risk of specific mutant proteins in a large cohort of anonymous DNA samples from specific drug addictions, stratified for age, gender, race/ethnicity to compare with matched controls. Collectively, these experimental aims seek to validate naturally occurring FAAH genetic variants as predictors of vulnerability to drug abuse and dependence so that individuals at greatest risk may be identified early and treatment strategies tested for this major public health problem.