Circadian Clock Genes in Bipolar Disorder

双相情感障碍中的昼夜节律时钟基因

• 批准号: 8598045
• 负责人: Michael Joseph McCarthy
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598045
• 关键词: Address; Adverse effects; Affect; Bioinformatics; Biological; Biological Psychiatry; Bioluminescence; Bipolar Disorder; Cell Culture Techniques; Cell Line; Cells; Chronobiology; Circadian Rhythms; Clinical; Cultured Cells; Diagnosis; Diagnostic tests; Doctor of Medicine; Doctor of Philosophy; Ethics; Fibroblasts; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Epistasis; Genetic Variation; Genetic screening method; Genotype; Goals; Healthcare Systems; Hypothalamic structure; Individual; K-Series Research Career Programs; Lead; Life; Literature; Lithium; Measures; Medicine; Mental disorders; Mentally Ill Persons; Mentors; Methods; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Molecular Target; Mood Disorders; Morbidity - disease rate; Neurobiology; Neurosciences; Occupational; Other Genetics; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Population; Postdoctoral Fellow; Recording of previous events; Reporter; Reporter Genes; Research Activity; Sampling; Scientist; Signal Pathway; Skin; Sleep; Small Interfering RNA; Stem cells; Symptoms; System; Techniques; Testing; Tissues; Training; Translational Research; Variant; Veterans; Work; base; circadian pacemaker; cohort; cost; density; genetic analysis; genetic association; genetic variant; improved; inhibitor/antagonist; insight; interest; knock-down; meetings; molecular site; mortality; psychogenetics; response; skills; social; suprachiasmatic nucleus; treatment response

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.

描述（由申请人提供）： 双相情感障碍（BD）是一种威胁生命的精神疾病，影响了1-2％的人口，包括约100,000名退伍军人。在反应敏感的患者中，锂是BD的出色治疗方法，但是许多患者无法反应，并且不必要地遭受副作用或延迟失败的治疗或误诊。因此，可以快速诊断BD并识别锂反应者的新技术将具有临床实用性。 锂具有几种生物学作用。其中，它改变了基因表达和昼夜节律，包括在BD中破坏的节奏。昼夜节律的时钟由一个相互作用的基因网络组成，该网络在约24小时的周期中保持节奏。虽然下丘脑的上核核是昼夜节律的“主时钟”，但时钟基因在外周组织中起作用，并且可以在培养的皮肤细胞（成纤维细胞）中进行研究。我们采用了专门的记者基因来促进这些研究。记者可以插入培养的细胞中，可以通过测量生物发光来在几天内用于研究昼夜节律。使用这种方法，可以准确研究BD患者的组织中的昼夜节律。 昼夜节律研究可能会提供有关锂如何处理BD的见解。通过了解锂的作用，可以开发治疗反应的预测因子或开发新药物。该职业发展奖提出的工作（CDA2）旨在识别：1）影响锂反应的时钟基因中的变体2）遗传变异对时钟功能的影响； 3）锂在时钟内的作用源。我将采用两种方法来解决以下问题：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，并在锂处理的BD患者中进行遗传关联研究。 申请人是M.D.和Ph.D.生物精神病学的博士后研究员。 （神经科学）学位。该CDA2的短期目标将是他从临床培训到转化研究独立性的过渡。通过研究BD中的时钟基因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领域的高级概念和技术的额外培训。为了实现培训目标，已经制定了一项详细的计划，其中包含了一般和专业活动。这些包括拟议的研究活动支持的教学和应用基于问题的方法。 CDA2的联合官员是Kelsoe博士和威尔士，分别是精神遗传学和昼夜节律的公认专家。申请人还将获得Drs Dunn，Gage和Ideker博士的额外培训，他们将监督基因检测，基于BD的干细胞模型的伦理学培训以及对遗传相互作用的生物信息学分析。这项工作将在圣地亚哥VA医疗保健系统内进行，并与UCSD的隶属关系，UCSD是一个学术中心，以其在精神遗传学，神经生物学和时间生物学方面的优势而认可。凭借这些增加的技能，申请人的长期目标是在情绪障碍的分子遗传学方面发展专业知识，并充当医生科学家，以开发基于生物学的方法来治疗精神疾病；历史上证明，这种方法可以改善其他医学领域的治疗方法。