GENETICS AND CONSEQUENCES OF NICOTINE ADDICTION

描述(由申请人提供)：这是犹他大学教职员工提出的关于尼古丁成瘾的遗传学和后果的项目资助(PPG)的修订申请。该PPG的广泛目标是系统地剖析成瘾的遗传和分子机制，并确定尼古丁在吸烟造成的破坏性临床疾病中的作用，确定最终可以被操纵的特定方面，以预防和/或有效地治疗这种毁灭性的痛苦。正在测试的主题假设是，尼古丁成瘾及其后果的易感性具有潜在的遗传成分。在这一假说中，烟碱型乙酰胆碱受体(NAChRs)在决定成瘾的易感性和吸烟的后果中起着关键作用，包括导致慢性阻塞性肺疾病(COPD)的失调炎症和异常修复。这一假说将通过使用强大的犹他州家族数据库和成熟的COPD数据库对候选基因和连锁分析的研究与使用小鼠遗传学和生物学的研究相结合来解决。这些研究旨在产生新的知识，以提高我们对成瘾及其后果的遗传学的理解。在PPG中，具有良好互动记录的富有成效的资深调查人员联合指导了三个项目和四个核心。每个项目都涉及新的机制，并以中心主题为导向。每个项目都有新的初步数据支持，这些数据记录了拟议研究的重要性和可行性。我们相信，该提案提供了成熟的研究计划、经过验证的多学科协作互动以及丰富的基础和临床研究环境的特殊优势。 通过以成瘾及其后果的遗传学为导向，这三个项目几乎在研究的每一个阶段都相互作用，本质上相互加强。PPG的“智能结构”如下：项目1，结合使用独特的患者群体和用于基因分型和大规模核苷酸测序的“最先进”技术，以调查人类尼古丁成瘾的遗传学。项目2是对项目I研究的补充，它利用具有良好特性的近交系小鼠和基因靶向方法，描绘了有助于通过nAChRs形成和维持对尼古丁耐受性的遗传机制。项目3使用项目I中采用的遗传方法和项目2中使用的近交系小鼠品系开发的动物模型来探索尼古丁在COPD发病机制中的作用和COPD的遗传基础。一个行政核心、一个动物核心、一个微阵列核心和一个重新测序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调整，力度要大得多。它提供在多学科协作互动中聚集在一起的既定研究计划，在一个重要的社会问题上进行生产性的基础和临床研究。

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.