Repurposing cholinesterase inhibitors for smoking cessation

描述（由申请人提供）：作为一名临床心理学家，我的长期职业目标是在以患者为导向的研究（POR）中建立一个独立的职业生涯，该研究专注于开发和评估更有效的尼古丁依赖治疗方法，特别是减少戒断相关认知缺陷的治疗方法（称为促认知治疗）。我之前的培训使我能够发展提供FDA批准的戒烟治疗和进行人体实验室研究的技能。我的研究生和实习培训主要集中在心理生理学，压力反应和尼古丁依赖。作为一名博士后研究员，我已经将这种培训扩展到尼古丁依赖治疗研究和神经认知研究。然而，为了实现我的长期职业目标，我必须解决我在知识和培训方面的关键差距。2012年7月1日，我 我将被任命为宾夕法尼亚大学精神病学系的助理教授，这将使我开始在认知和戒烟治疗方面追求独立的职业生涯。K23机制将使我能够集中至少90%的时间和精力来发展作为独立临床研究人员的职业生涯。我的培训目标以合乎逻辑的方式进行，为我过渡到该领域的独立研究生涯做好准备。其中包括：1）获得神经药理学和认知神经科学的新知识，以了解尼古丁依赖治疗的疗效机制，特别是促认知药物; 2）进行研究项目，以评估促认知药物是否逆转戒断相关的认知缺陷并提高戒烟率;以及3）发展必要的技能来交流我的研究成果，以确保后续的研究资金，并在跨学科的环境中进行合作。我将通过相关的课程，指导我的导师和指导委员会的指导，参加研讨会和讲习班，以及应用实践研究培训来实现这些培训目标。这种多模式的方法将使我能够获得对我的职业目标至关重要的领域的新知识（例如，神经药理学和认知神经科学），实施拟议的研究计划，并建立一个独立的研究计划，目标是在K23奖结束前获得R 01。该研究项目是一项概念验证研究，旨在研究一种新型药物治疗加兰他敏对戒烟的影响，加兰他敏是一种乙酰胆碱酯酶抑制剂（ACHEI），FDA批准用于治疗阿尔茨海默病的认知症状。测试加兰他敏的科学原理基于以下证据：（a）认知缺陷预测吸烟复发;（B）加兰他敏减少啮齿动物中尼古丁自我给药并减弱戒断相关认知缺陷;和（c）加兰他敏在阿尔茨海默病患者中具有促认知作用。此外，我使用加兰他敏治疗寻求治疗的吸烟者的初步数据支持这种戒烟治疗方法。这项拟议的研究利用了一个短期戒烟的II期模型，该模型已被证明对早期人类戒烟药物筛查具有临床有效性。在这项随机平行组试验中，我将比较加兰他敏与安慰剂对寻求治疗的吸烟者戒断相关认知缺陷和短期戒烟成功的影响。由于现有FDA批准的戒烟治疗方法疗效有限，因此该项目可能会产生重要的临床影响。宾夕法尼亚大学（UPenn）尼古丁成瘾跨学科研究中心（CIRNA）的环境具有独特的装备，可以支持我的培训需求。我将由Caryn Lerman博士指导。（CIRNA主任，主要导师）和医学博士亨利克兰兹勒。（共同主任，成瘾研究中心，共同导师）。我的导师委员会包括神经药理学、遗传学和神经科学领域的科学家。指导将通过重点课程和参加在宾夕法尼亚大学的研讨会和讲习班来补充。除了这些智力资源外，CIRNA还将提供开展研究所需的实用资源，包括使用广泛的基础设施进行参与者招募、医学筛查、数据管理和生物统计支持。通过CIRNA提供的额外财政支持将使我有90%的保护时间作为精神病学系的新助理教授进行拟议的培训和研究，并发展我的职业生涯。这种全面的，跨学科的指导方法将提高我的临床研究技能和我的能力，成功地竞争R 01资金，并建立一个独立的研究计划。

DESCRIPTION (provided by applicant): As a clinical psychologist, my long-term career goal is to establish an independent career in patient-oriented research (POR), which focuses on the development and evaluation of more efficacious treatments for nicotine dependence, specifically treatments that reduce withdrawal-related cognitive deficits (referred to as pro-cognitive treatments). My prior training has enabled me to develop skills in delivering FDA-approved smoking cessation treatments and conducting human laboratory studies. My graduate and internship training focused primarily on psychophysiology, stress responses, and nicotine dependence. As a postdoctoral fellow, I have extended this training to nicotine dependence treatment research and neuro-cognitive research. However, to achieve my long-term career goal, it is essential that I address critical gaps in my knowledge and training. On July 1, 2012, I will be appointed Assistant Professor in the Department of Psychiatry at UPenn, which will allow me to begin my pursuit of an independent career in POR on cognition and smoking cessation treatment. The K23 mechanism will enable me to focus at least 90% of my time and effort to develop a career as an independent clinical researcher. My training objectives progress in a logical fashion to prepare me for the transition to an independent research career in this area. These include: 1) acquiring new knowledge in neuro-pharmacology and cognitive neuroscience to understand the mechanisms of efficacy of nicotine dependence treatments, particularly pro- cognitive medications; 2) conducting a research project to evaluate whether a pro-cognitive medication reverses withdrawal-related cognitive deficits and improves quit rates; and 3) developing the skills necessary to communicate my research findings, to secure subsequent research funding, and to collaborate in an interdisciplinary environment. I will accomplish these training objectives through relevant coursework, guidance from my mentor and mentorship committee, attendance at seminars and workshops, and applied hands-on research training. This multi-modal approach will enable me to acquire new knowledge in areas essential to my career goals (e.g., neuro-pharmacology and cognitive neuroscience), implement the proposed research plan, and build an independent research program with the goal of receiving an R01 prior to the end of the K23 award. The research project is a proof-of-concept study designed to examine the effects on smoking cessation of a novel pharmacological treatment, galantamine, an acetylcholinesterase inhibitor (ACHEI) that is FDA-approved to treat the cognitive symptoms of Alzheimer's disease. The scientific rationale for testing galantamine is based on evidence that: (a) cognitive deficits predict smoking relapse; (b) galantamine reduces nicotine self- administration and attenuates withdrawal-related cognitive deficits in rodents; and (c) galantamine has pro- cognitive effects in Alzheimer's disease patients. Further, my preliminary data using galantamine with treatment-seeking smokers supports this approach for smoking cessation treatment. The proposed study utilizes a Phase II model of short-term quitting that has been shown to be clinically valid for early human screening of smoking cessation medications. In this randomized, parallel-arm trial, I will compare the effects of galantamine with placebo on withdrawal-related cognitive deficits and short-term quitting success in treatment- seeking smokers. Because existing FDA-approved treatments for smoking cessation have limited efficacy, this project could have an important clinical impact. The environment at the Center for Interdisciplinary Research on Nicotine Addiction (CIRNA) at the University of Pennsylvania (UPenn) is uniquely equipped to support my training needs. I will be mentored by Caryn Lerman, Ph.D. (CIRNA Director, primary mentor) and Henry Kranzler, M.D. (Co-Director, Center for Studies of Addiction, co-mentor). My mentorship committee includes scientists in the areas of neuropharmacology, genetics, and neuroscience. Mentorship will be complemented by focused coursework and participation in seminars and workshops at UPenn. In addition to these intellectual resources, CIRNA will provide the practical resources needed to conduct my research, including use of an extensive infrastructure for participant recruitment, medical screening, data management, and biostatistical support. Additional financial support provided through CIRNA will enable me to have 90% protected time as a new Assistant Professor in the Department of Psychiatry to conduct the proposed training and research and to develop my career. This comprehensive, interdisciplinary mentored approach will enhance my clinical research skills and my ability to compete successfully for R01 funding and establish an independent program of research.