Identification of genes involved in the lithium-responsive neurological process

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，BPD是一种慢性和致残性精神疾病，影响美国200多万人。了解锂的治疗作用将为BPD的病因学和病理生理学提供重要的见解，并有助于开发更好的治疗这种严重疾病。这项研究的目的是以果蝇为模式生物，阐明锂离子反应神经通路中的分子和细胞机制。果蝇突变体Shudderer（Shu）是一种X连锁显性突变体，其表现出多种神经学表型，包括多动、不协调运动、偶尔发生的抽搐和麻醉诱导的癫痫发作。有趣的是，这些表型中的许多表型被锂大大抑制，其内部浓度用于治疗BPD患者。此外，舒可能与糖原合成酶激酶3基因在功能上相互作用，该基因与锂的治疗作用有关。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）鉴定与Shu功能性相互作用的基因。为了实现Aim-1，将使用基于重组的高分辨率作图方法和分子定义的P元件插入，将Shu突变的位置绘制在一个小的基因组区域（<50 kb）中。将鉴定Shu基因，并通过对从完全等基因化的Shu突变果蝇中分离的基因组DNA进行测序来确定突变的分子性质。携带野生型或突变形式的Shu基因的转化体将用于确认基因的身份。对于Aim-2，将分子定义的缺陷和突变引入Shu突变体背景中，以鉴定Shu突变的抑制子和增强子。这项申请中提出的研究具有重要意义，因为对Shu突变体的研究有望为神经系统中锂响应过程的遗传成分提供新的知识。基于果蝇和脊椎动物之间基本的分子和细胞机制非常保守的事实，这些发现也有望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，这将为未来开发新的和改进的BPD疗法开辟可能性。

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.