Role of Beta2-nAChR in Bipolar Disorder

描述（由申请人提供）：此K 01申请提出了对Esterlis博士职业发展至关重要的支持，因为她过渡到情绪和共病物质使用障碍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，增加情绪障碍和情绪物质障碍合并症的专业知识，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）脑成像方法的严格培训，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。培训将包括在精神病学和放射学，校内和校外教学，在科学会议和手稿和赠款提交演示部门的导师和合作者的个人会议的整合。 该项目的科学重点是研究一种可能参与双相情感障碍（BD）和烟草依赖共病的病理生理学的新机制。与一般人群相比，BD中烟草依赖的流行率是普通人群的三倍，然而，这种合并症背后的原因尚未得到很好的理解，也没有针对BD中戒烟或相关抑郁症状的有效治疗方法。因此，迫切需要研究新的药理学靶点的分子机制。新出现的证据表明，烟碱乙酰胆碱受体（nAChR）系统在BD的病理生理学及其情绪和认知症状。因此，我们提出了一个创新的研究吸烟和BD的情绪和认知功能障碍之间的关系，这可能是由nAChR系统的22亚基介导的。患有BD的非吸烟者（n=20）和吸烟者（n=20）以及匹配的对照将参与[123 I]5-IA-85380 SPECT扫描，以确定22-nAChR的可用性。吸烟者将在戒烟前、戒烟24小时后、SPECT扫描当天再次接受情绪和认知评估，非吸烟者则在相应时间接受情绪和认知评估。将测量BD与对照组以及BD吸烟者与非吸烟者的22-nAChR的幅度和分布差异。将评估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型谷氨酸能系统（mGluR 5）在相同BD受试者中的分布数据，并将使BD中多受体参与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.