Identification of genes involved in lithium-responsive

锂反应相关基因的鉴定

• 批准号: 7137225
• 负责人: TOSHIHIRO KITAMOTO
• 金额: $ 7.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7137225
• 关键词: Drosophilidae; arthropod genetics; behavioral /social science research tag; behavioral genetics; biotechnology; bipolar depression; gene interaction; gene mutation; genetic mapping; genetic susceptibility; lithium; molecular genetics; pharmacogenetics; phenotype; psychopharmacology; serine threonine protein kinase

DESCRIPTION (provided by applicant): Lithium has been used as the highly effective therapy for bipolar disorder (BPD), a chronic and disabling mental illness that affects more than 2 million people in the US. Understanding the therapeutic action of lithium would provide important insight into the etiology and pathophysiology of BPD, and help to develop better treatment for this serious disease. The goal of the proposed research is to elucidate molecular and cellular mechanisms involved in the lithium-responsive neurological pathway using the fruit fly as a model organism. A Drosophila mutant Shudderer (Shu) is an X-linked dominant mutant that exhibits various neurological phenotypes, including hyperactivity, uncoordinated movements, sporadically occurring jerks and anesthesia-induced seizure. Interestingly, many of these phenotypes are greatly suppressed by lithium with the internal concentrations used for treatment of BPD patients. In addition, Shu may functionally interact with the glycogen synthase kinase 3 gene that has been implicated in the lithium therapeutic action. Specific aims of this proposal are to: 1) identify the Shu gene and determine the molecular nature of the Shu mutation and; 2) identify genes that functionally interact with Shu. To accomplish the Aim-1, the location of the Shu mutation will be mapped in a small genomic region (<50 kb) using a high-resolution recombination-based mapping approach with molecularly defined P element insertions. The Shu gene will be identified and the molecular nature of the mutation will be determined by sequencing the genomic DNA isolated from the fully isogenized Shu mutant flies. Transformants carrying either a wild type or a mutant form of the Shu gene will be used to confirm the identity of the gene. For Aim-2, the molecularly defined deficiencies and mutations will be introduced into the Shu mutant background to identify suppressors and enhancers for the Shu mutation. The research proposed in this application is significant, because studies of the Shu mutant are expected to provide novel knowledge of genetic components underlying the lithium-responsive process in the nervous system. Based on the fact that the fundamental molecular and cellular mechanisms are well conserved between the fruit fly and vertebrates, the findings are also expected to lead to the recognition of uncharacterized players or processes responsible for the lithium action in the vertebrates, which would open up the future possibility to develop novel and improved therapies for BPD.

描述（由申请人提供）：锂已被用作双相情感障碍 (BPD) 的高效疗法，双相情感障碍是一种慢性致残性精神疾病，在美国影响着超过 200 万人。了解锂的治疗作用将为了解 BPD 的病因学和病理生理学提供重要的见解，并有助于为这种严重疾病开发更好的治疗方法。拟议研究的目标是使用果蝇作为模型生物来阐明锂响应神经通路所涉及的分子和细胞机制。果蝇突变体 Shudderer (Shu) 是一种 X 连锁显性突变体，表现出各种神经表型，包括多动、运动不协调、偶发性抽搐和麻醉引起的癫痫发作。有趣的是，许多这些表型都被用于治疗 BPD 患者的内部浓度的锂极大地抑制。此外，Shu 可能与参与锂治疗作用的糖原合酶激酶 3 基因发生功能性相互作用。该提案的具体目标是：1）鉴定 Shu 基因并确定 Shu 突变的分子性质； 2) 识别与 Shu 功能相互作用的基因。为了实现 Aim-1，将使用基于高分辨率重组的定位方法和分子定义的 P 元件插入，将 Shu 突变的位置定位在一个小的基因组区域 (<50 kb)。通过对从完全同源化的 Shu 突变果蝇中分离的基因组 DNA 进行测序，将鉴定 Shu 基因并确定突变的分子性质。携带野生型或突变型 Shu 基因的转化体将用于确认该基因的身份。对于 Aim-2，分子定义的缺陷和突变将被引入 Shu 突变体背景中，以识别 Shu 突变的抑制子和增强子。本申请中提出的研究意义重大，因为对 Shu 突变体的研究有望提供有关神经系统锂响应过程背后的遗传成分的新知识。基于果蝇和脊椎动物之间基本的分子和细胞机制得到良好保守的事实，这些发现预计还将导致对脊椎动物中负责锂作用的未表征的参与者或过程的认识，这将打开未来开发新的和改进的 BPD 疗法的可能性。