Circadian Clock Genes in Bipolar Disorder

描述（由申请人提供）： 双相情感障碍（BD）是一种危及生命的精神疾病，影响1-2%的人口，包括约10万退伍军人。在有反应的患者中，锂是治疗BD的一种很好的方法，但许多患者没有反应，并且由于治疗不成功或误诊而不必要地遭受副作用或延误。因此，快速诊断BD和鉴定锂反应者的新技术将具有临床实用性。 锂具有多种生物学效应。其中，它改变了基因表达和昼夜节律，包括在BD中被破坏的那些。生物钟是由一个相互作用的基因网络组成的，这些基因在大约24小时的周期内维持节律。虽然下丘脑的视交叉上核是昼夜节律的“主时钟”，但时钟基因在外周组织中具有功能，并且可以在培养的皮肤细胞（成纤维细胞）中进行研究。我们采用专门的报告基因，以促进这些研究。报道分子可以插入培养的细胞中，通过测量生物发光来研究几天内的昼夜节律。使用这种方法，可以准确地研究BD患者组织中的生物钟。 昼夜节律研究可能会提供有关锂如何治疗BD的见解。通过了解锂的作用，有可能开发治疗反应的预测因子，或开发新的药物。这项职业发展奖（CDA 2）的工作旨在确定：1）影响锂反应的时钟基因变异2）遗传变异对时钟功能的影响3）时钟内锂作用的位点。我将采用两种方法来解决这些问题：1）在BD患者的细胞培养物中使用生物发光报告基因测量基因表达，2）在锂治疗的BD患者中进行遗传关联研究。 申请人是生物精神病学博士后研究员，和博士神经科学学位。该CDA 2的短期目标将是完成从临床培训到转化研究独立性的转变。通过研究生物钟基因如何在BD中发生故障，以及锂如何与它们相互作用，他将获得遗传学和神经生物学先进概念和技术的额外培训。为了实现培训目标，制定了一项包括一般和专门活动的详细计划。这些包括教学和应用的问题为基础的方法，是由拟议的研究活动的支持。CDA 2的共同导师是Drs Kelsoe和Welsh，他们分别是精神遗传学和昼夜节律方面的公认专家。申请人还将接受Dunn，Gage和Ideker博士的额外培训，他们将监督遗传检测，BD干细胞模型和遗传相互作用的生物信息学分析的伦理学培训。这项工作将在圣地亚哥VA医疗保健系统内进行，与UCSD合作，UCSD是一个以其在精神病学遗传学，神经生物学和时间生物学方面的优势而闻名的学术中心。有了这些额外的技能，申请人的长期目标是发展情绪障碍的分子遗传学专业知识，并作为一名医生-科学家开发基于生物学的方法来治疗精神病患者;这种方法在历史上已被证明在其他医学领域的改善治疗中产生效果。

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a life-threatening mental illness that affects 1-2% of the population, including ~100,000 veterans. In responsive patients, lithium is an excellent treatment for BD, but many patients fail to respond and needlessly suffer side-effects or delays from unsuccessful treatment or misdiagnosis. Therefore new techniques to rapidly diagnose BD and identify lithium responders would be of clinical utility. Lithium has several biological effects. Among these, it alters gene expression and circadian rhythms, including those disrupted in BD. The circadian clock is comprised of an interacting network of genes that maintain rhythms over ~24 hr cycles. While the suprachiasmatic nucleus of the hypothalamus is the "master clock" for circadian rhythms, clock genes are functional in peripheral tissues and can be studied in cultured skin cells (fibroblasts). We have employed specialized reporter genes to facilitate these studies. Reporters can be inserted into cultured cells where they can be used to study circadian rhythms over several days by measuring bioluminescence. Using this approach, one can accurately study the circadian clock in tissues from BD patients. Circadian rhythms studies may provide insights into how lithium works to treat BD. By understanding lithium's actions it may be possible to develop predictors of treatment response, or to develop new medications. The work proposed for this career development award (CDA2) aims to identify: 1) Variants in clock genes that influence lithium response 2) Effects of genetic variants on clock function and 3) The locus of lithium's action within the clock. I will employ two methods to address these questions: 1) Measure gene expression using bioluminescent reporter genes in cell cultures from BD patients and 2) Perform genetic association studies in lithium-treated BD patients. The applicant is a post-doctoral fellow in biological psychiatry with both M.D. and Ph.D. (Neuroscience) degrees. The short-term goal of this CDA2 will be complete his transition from clinical training to translational research independence. By studying how clock genes malfunction in BD, and how lithium interacts with them, he will get additional training in advanced concepts and techniques in genetics and neurobiology. In order to meet the training goals, a detailed plan incorporating general and specialized activities has been developed. These include didactic and applied problem-based approaches that are supported by the proposed research activity. The co-mentors for the CDA2 are Drs Kelsoe and Welsh, recognized experts in psychiatric genetics and circadian rhythms respectively. The applicant will also receive additional training from Drs Dunn, Gage and Ideker who will oversee training in ethics of genetic testing, stem-cell based models of BD, and bioinformatic analysis of genetic interactions. The work will be conducted within the San Diego VA Healthcare System, in affiliation with UCSD, an academic center recognized for its strengths in psychiatric genetics, neurobiology and chronobiology. With these added skills, the applicant's long-term goal is to develop expertise in the molecular genetics of mood disorders and function as a physician-scientist to develop biologically-based approaches to treating the mentally ill; an approach that has historically shown to yield results in improved treatment in other fields of medicine.