Role of Beta2-nAChR in Bipolar Disorder

描述(由申请人提供)：这份K01申请书提出了对Esterlis博士的职业发展至关重要的支持，因为她正在过渡到一名情绪和共病物质使用障碍的神经感受器成像方面的独立研究员。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在单光子发射计算机断层扫描(SPECT)和正电子发射断层扫描(PET)脑成像方法方面的严格培训，包括噪声校正技术和定量技能，并将这些技术应用于情绪障碍的生物学基础的神经成像。培训将包括与精神病学系和放射学系的导师和合作者、校内和校外教学、在科学会议上的陈述以及提交的手稿和赠款的个别会议。该项目的科学重点是研究一种新的机制，该机制可能涉及双相情感障碍(BD)和共病烟草依赖的病理生理学。烟草依赖在BD中的流行程度是普通人群的三倍，然而，这种共病背后的原因还没有被很好地理解，也没有公认的有效治疗BD的戒烟或相关的抑郁症状。因此，迫切需要研究新的药物治疗靶点的分子机制。新的证据表明，烟碱型乙酰胆碱受体(NAChR)系统与BD及其情绪和认知症状的病理生理学有关。因此，我们提出了一项关于吸烟与BD患者情绪和认知功能障碍之间关系的创新性研究，这可能是由nAChR系统的22个亚基介导的。患有BD和匹配对照组的非吸烟者(n=20)和吸烟者(n=20)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、戒烟后24小时、在SPECT扫描当天再次进行情绪和认知评估，并在相应的时间对非吸烟者进行评估。将测量BD组和对照组以及BD吸烟者和不吸烟者之间22-nAChR的大小和分布的差异。我们将评估情绪和认知症状之间的关系。{{此外，拟议的职业培训项目将提供有关代谢性谷氨酸能系统(MGluR5)在相同的BD受试者中分布的数据，并将使对BD中多受体参与的独特调查成为可能。

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.