GENETICS AND CONSEQUENCES OF NICOTINE ADDICTION

尼古丁成瘾的遗传学和后果

• 批准号: 6948503
• 负责人: John R Hoidal
• 金额: $ 235.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948503
• 关键词: chronic obstructive pulmonary disease; clinical research; disease /disorder proneness /risk; drug addiction; family genetics; genetic susceptibility; human subject; laboratory mouse; nicotine; nicotinic receptors; patient oriented research; smoking; tobacco abuse

DESCRIPTION (provided by applicant): This is a revised application from faculty members at the University of Utah for support of a Program Project Grant (PPG) on the genetics and consequences of nicotine addiction. The broad objective of this PPG is to systematically dissect the genetic and molecular mechanisms of addiction and to determine the role of nicotine in the devastating clinical conditions caused by cigarette smoking, identifying specific facets that can ultimately be manipulated to prevent and/or effectively treat this devastating affliction. The thematic hypothesis being tested is that the susceptibility to both nicotine addiction and its consequences has underlying genetic components. In this hypothesis, nicotinic acetylcholine receptors (nAChRs) are critically involved in initiating the determining susceptibility to addiction and the consequences of cigarette smoking, including the dysregulated inflammation and abnormal repair that lead to chronic obstructive pulmonary disease (COPD). The hypothesis will be addressed by combining studies of candidate gene and linkage analysis using the powerful Utah family database and a well-established COPD database with studies using mouse genetics and biology. The studies are designed to generate new knowledge that will improve our understanding of the genetics of addiction and its consequences. In the PPG, productive established investigators with excellent track records of interaction have combined to direct three projects and four cores. Each project addresses novel mechanisms and is oriented around the central theme. Each project is supported by new preliminary data that document the importance and feasibility of the proposed studies. We believe that the proposal offers the special advantages of established research programs, proven multidisciplinary collaborative interactions and a rich environment for productive basic and clinical research. By orienting the proposal around the genetics of addiction and its consequences, all three projects interact and intrinsically reinforce each other in almost every phase of their studies. The "intellectual structure" of the PPG is as follows: Project 1, combines the use of unique patient populations with "state of the art" techniques for genotyping and large scale nucleotide sequencing to investigate the genetics of nicotine addiction in humans. Project 2 complements the studies of Project I by delineating the genetic mechanisms that contribute to the formation and maintenance of tolerance to nicotine through nAChRs using well-characterized inbred mice and gene-targeting approaches. Project 3 uses the genetic approaches employed in Project I and animal models developed in the inbred mouse strains used in Project 2 to explore the role of nicotine in the pathogenesis of COPD and the genetic basis for COPD. An Administrative Core, an Animal Core, a Microarray Core and a Resequencing and Genomic Analysis Core support the three projects. The revised proposal has been restructured in response to the initial review and is much stronger. It offers established research programs coming together in multi-disciplinary collaborative interactions for productive basic and clinical research on an important societal problem.

描述（由申请人提供）：这是犹他大学教职员工的修订申请，以支持尼古丁成瘾的遗传学和后果计划项目赠款（PPG）。该PPG的广泛目标是系统地剖析成瘾的遗传和分子机制，并确定尼古丁在香烟吸烟引起的毁灭性临床条件中的作用，确定最终可以操纵和/或有效治疗这种毁灭性苦难的特定方面。测试的主题假设是，对尼古丁成瘾及其后果的敏感性具有潜在的遗传成分。在这一假设中，烟碱乙酰胆碱受体（NACHR）与确定对成瘾的易感性和吸烟的后果（包括失调的炎症和异常修复，导致慢性阻塞性肺部疾病（COPD），包括炎症和吸烟的后果。该假设将通过使用强大的犹他州家族数据库和良好的COPD数据库与使用小鼠遗传学和生物学的研究结合候选基因和连锁分析的研究来解决该假设。这些研究旨在产生新知识，以提高我们对成瘾遗传学及其后果的理解。在PPG中，具有出色互动记录的富有成效的研究人员结合了三个项目和四个核心。每个项目都涉及新颖的机制，并围绕中心主题而定向。每个项目都得到新的初步数据的支持，这些数据记录了拟议研究的重要性和可行性。我们认为，该提案提供了既定的研究计划的特殊优势，经过验证的多学科协作互动以及为生产性基础和临床研究提供丰富的环境。 通过围绕成瘾的遗传学及其后果的提议，这三个项目几乎在他们的研究的每个阶段几乎都会互相增强。 PPG的“智力结构”如下：项目1，将独特的患者种群与“先进状态”技术结合了基因分型和大规模核苷酸测序，以研究人类尼古丁成瘾的遗传学。项目2通过描述使用良好的近交小鼠和靶向基因靶向方法来促进对尼古丁形成和维持尼古丁的耐受性的遗传机制，从而补充了项目I的研究。项目3使用项目I和动物模型中在项目2中使用的近交小鼠菌株中开发的动物模型中采用的遗传方法，以探索尼古丁在COPD发病机理和COPD的遗传基础中的作用。行政核心，动物核心，微阵列核心以及重新陈述和基因组分析核心支持这三个项目。 修订后的提案已根据初步审查进行了重组，并且要强得多。它提供了既定的研究计划，共同融合了多学科的合作互动，用于有关重要社会问题的生产性基础和临床研究。