FAAH GENE MUTATIONS: RISK FACTORS IN DRUG USE/ADDICTION

FAAH 基因突变：吸毒/成瘾的风险因素

• 批准号: 6864827
• 负责人: JACK C SIPE
• 金额: $ 28.16万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864827
• 关键词: age difference; barbiturates; cannabinoid receptor; drug abuse; drug abuse information system; drug addiction; gender difference; gene expression; gene mutation; genetic library; genetic susceptibility; hallucinogens; human genetic material tag; inhalation drug abuse; mass spectrometry; narcotics; nicotine; nucleic acid hybridization; opiate alkaloid; oxygenases; polymerase chain reaction; racial /ethnic difference; recombinant proteins; sedative /hypnotic; single nucleotide polymorphism; western blottings

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.

描述（由申请人提供）：吸毒成瘾对受影响的个人，其家庭和文明社会造成了巨大损失。这项基础研究提案是针对PA＃00-115的回应，通过识别，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，脂肪酸酰胺水解酶（FAAH）的主要分解代谢机构的内源性分解代谢剂水平和脑内源性大麻素系统（ECS）的疾病可能有助于这种遗传的疾病。 大脑ECS是一种最近发现但进化的古代逆行信号通路，具有连续调节（下调）神经递质释放的能力，包括许多关键的神经元系统，包括中漏多巴胺成瘾/奖励系统。早就知道，在某些脆弱的个体中，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着作用。由于脑内源性大麻素具有与外源性大麻相同的受体靶标和活性，因此该提案的中心假设是，FAAH的功能异常遗传变异可能会导致对药物滥用和成瘾的脆弱性的风险。该提案的长期目标和目的是在具有特定类型的药物滥用类型的匿名受试者中识别和测试生化的大法官突变，并将这些突变与易受药物滥用或依赖性的危险因素联系起来。 该提案的重点是在人类法族基因的初步研究中鉴定出的基因突变。 该计划是在遗传，生物化学和功能上评估重要的人faaH突变，并确认来自特定药物成瘾的大量匿名DNA样本在大量的匿名DNA样本中确认特定突变蛋白的风险，并分层年龄，性别，种族/种族/种族/种族与匹配的控制相比。 总的来说，这些实验目的试图验证自然发生的FAAH遗传变异，以预测吸毒和依赖性的脆弱性，以便可以尽早确定处于最大风险的个人，并对这一主要的公共卫生问题进行了治疗策略。