Role of Beta2-nAChR in Bipolar Disorder

描述（由申请人提供）：这份K01申请为Esterlis博士的职业发展提供了必要的支持，因为她过渡到情绪和共病物质使用障碍的神经受体成像的独立研究者。拟议的职业奖励计划旨在促进她作为神经成像专家的科学发展，增加在情绪障碍和情绪-物质障碍共病方面的专业知识，包括进行两项独特的受体成像研究。Esterlis博士的职业发展计划侧重于对单光子发射计算机断层扫描（SPECT）和正电子发射断层扫描（PET）脑成像方法的严格训练，包括噪声校正技术和定量技能，以及将这些技术应用于情绪障碍生物学基础的神经成像。培训将包括与精神病学和放射学系的导师和合作者的个人会议、校内和校外教学、在科学会议上的演讲以及手稿和赠款的提交。该项目的科学重点是研究可能涉及双相情感障碍（BD）和共病烟草依赖病理生理的新机制。与一般人群相比，双相障碍患者中烟草依赖的发生率是其三倍，然而，这种共病背后的原因尚不清楚，也没有行之有效的双相障碍戒烟或相关抑郁症状的有效治疗方法。因此，迫切需要研究药物治疗靶点的新分子机制。新出现的证据暗示烟碱乙酰胆碱受体（nAChR）系统参与双相障碍及其情绪和认知症状的病理生理。因此，我们提出了一项关于吸烟与双相障碍患者情绪和认知功能障碍之间关系的创新研究，这可能是由nAChR系统的22个亚基介导的。患有BD的非吸烟者（n=20）和吸烟者（n=20）以及匹配的对照组将参加[123I]5-IA-85380 SPECT扫描，以确定22-nAChR的可用性。对吸烟者在戒烟前、戒烟24小时后、SPECT扫描当天和非吸烟者在相应时间进行情绪和认知评估。将测量22-nAChR的大小和分布在BD组与对照组的差异，以及BD吸烟者与非吸烟者的差异。将评估其与情绪和认知症状的关系。{{{此外，拟议的职业培训项目将提供有关代谢性脑瘤能系统（mGluR5）在相同BD受试者中的分布的数据，并将使多受体参与BD的独特研究成为可能。

DESCRIPTION (provided by applicant): This K01 application proposes support essential for Dr. Esterlis' career development as she transitions to an independent investigator in neuroreceptor imaging of mood and comorbid substance use disorders. The proposed career award plan is designed to further her scientific development as an expert neuroimager, with increased expertise in mood disorders and mood-substance disorder comorbidity, including the conduct of two unique receptor imaging studies. Dr. Esterlis' career development plan focuses on rigorous training in methods of single photon emission computerized tomography (SPECT) and positron emission tomography (PET) brain imaging, including noise- correction techniques and quantitative skills, and application of these techniques to the neuroimaging of biological basis of mood disorders. Training will include an integration of individual meetings with mentors and collaborators in the Departments of Psychiatry and Radiology, intramural and extramural didactics, presentations at scientific meetings and manuscript and grant submissions. The scientific focus of the proposed project is the investigation of a novel mechanism that may be involved in the pathophysiology of bipolar disorder (BD) and comorbid tobacco dependence. Tobacco dependence is three times as prevalent in BD as compared to general population, however, the reasoning behind this comorbidity is not well understood nor are there well-established efficacious treatments for smoking cessation or associated depression symptoms in BD. Thus, there is an urgent need for investigation of new molecular mechanisms for pharmacotherapeutic targets. Emerging evidence implicates the nicotinic acetylcholine receptor (nAChR) system in the pathophysiology of BD and its mood and cognitive symptoms. Thus, we propose an innovative study of the relationship between tobacco smoking and mood and cognitive dysfunction in BD, which may be mediated by the 22 subunit of the nAChR system. Nonsmokers (n=20) and smokers (n=20) with BD and matched controls will participate in a [123I]5-IA-85380 SPECT scan to determine 22-nAChR availability. Mood and cognitive assessments will be administered to smokers before smoking cessation, after 24h smoking cessation, and again on SPECT scan day, and at corresponding times to nonsmokers. Differences in the magnitude and distribution of the 22-nAChR in BD versus controls will be measured, as well as in BD smokers versus nonsmokers. Relationships to mood and cognitive symptoms will be assessed. {{{Furthermore, proposed career training project will provide data on the distribution of the metabotropic glumatamatergic system (mGluR5) in the same BD subjects and will enable a unique investigation of a multi-receptor involvement in BD.