GENETICS AND CONSEQUENCES OF NICOTINE ADDICTION

描述（由申请人提供）：这是犹他大学教师为支持一个关于尼古丁成瘾的遗传学和后果的项目项目拨款（PPG）而提交的修订申请。本PPG的总体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引起的破坏性临床状况中的作用，确定最终可以控制的具体方面，以预防和/或有效治疗这种毁灭性的痛苦。正在测试的主题假设是，对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，烟碱乙酰胆碱受体（nachr）在启动对成瘾和吸烟后果的决定易感性中起关键作用，包括导致慢性阻塞性肺疾病（COPD）的炎症失调和异常修复。该假设将通过使用强大的犹他家族数据库和完善的COPD数据库进行候选基因研究和连锁分析，以及使用小鼠遗传学和生物学研究来解决。这些研究旨在产生新的知识，以提高我们对成瘾的遗传学及其后果的理解。在PPG中，具有良好互动记录的富有成效的知名研究人员共同指导了三个项目和四个核心。每个项目都涉及新的机制，并围绕中心主题。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，该提案提供了建立研究项目的特殊优势，证明了多学科协作互动和丰富的生产基础和临床研究环境。

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.