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Studies of genes involved in the lithium responsive neurological processes

参与锂反应神经过程的基因研究

基本信息

批准号：
8420519
负责人：
TOSHIHIRO KITAMOTO
金额：
$ 32.08万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-04 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420519
关键词：
Adverse effects Affect Apoptosis Attention Binding Bipolar Disorder Brain Injuries Calcineurin Calmodulin Candidate Disease Gene Cessation of life Data Defect Development Down-Regulation Drosophila genus Drosophila melanogaster Etiology Functional disorder Future Gene Expression Profiling Genes Genetic Genetic Screening Genomics Goals Health Human Immune response Immune system Injury Lead Learning Lithium Metals Molecular Molecular Target Mood Disorders Moods Nervous System Physiology Nervous system structure Neurodegenerative Disorders Neurologic Neurons Neurophysiology - biologic function Organism Outcome Pattern Pharmaceutical Preparations Phenotype Physiology Play Prevention Process Property Public Health RNA Interference Research Role Severities Signal Transduction System Techniques Testing Therapeutic Therapeutic Effect Time Translating United States National Institutes of Health Up-Regulation Work base calcineurin phosphatase cell type effective therapy fly genetic variant genome wide association study genome-wide improved innovation insight interest mutant nervous system disorder novel overexpression prevent tool

项目摘要

DESCRIPTION (provided by applicant): Although lithium displays remarkable mood-stabilizing properties and has served as one of the most effective therapies for bipolar disorder (BPD), the mechanisms underlying its actions on the nervous system remain unclear. The long-term goal of this project is to understand-at the molecular and cellular levels-how lithium affects nervous system function. The objectives of this proposal are to identify genes that are involved in the lithium-responsive neurological process and to determine their roles in lithium's therapeutic action. To accomplish these objectives, we will utilize genetic tools that are uniquely available in the fruit fly Drosophila melanogaster. These include a neurological mutant Shudderer (Shu), whose phenotypes are largely rescued by lithium administration at therapeutic concentrations. Our central hypothesis, which is based on strong preliminary data, is that lithium reduces the severity of neurological defects caused by up-regulation of the Ca2????dependent phosphatase calcineurin, and that it does so by suppressing the innate immune response. The rationale for the proposed research is that, once the genes involved in lithium-responsive neurological processes in Drosophila have been identified and their roles have been revealed, this information should be readily translated into the vertebrate system, which is known to use signaling mechanisms that overlap extensively with those in Drosophila. Thus, our study is expected to provide novel and important insights into lithium's therapeutic action-with respect not only to BPD, but also other neurological disorders. Our central hypothesis will be tested by pursuing three specific aims: 1) Determine how up-regulation of calcineurin causes the lithium-responsive neurological defects; 2) Delineate the mechanisms responsible for lithium's therapeutic action on the Shu phenotype; and 3) Identify novel genes whose up- or down-regulation mimics lithium's actions in the nervous system. For the first aim, particular cell types and developmental timing of the calcineurin overexpression leading to the Shu phenotype will be defined by genetically manipulating calcineurin activity in a spatially and temporally specific manner. For the second aim, various genetic variants will be utilized to determine the extent to which the innate immune system is involved in manifestation of lithium-responsive neurological defects. For the third aim, molecularly defined mutants and RNAi will be employed to confirm the involvement of novel genes (from candidates that have been identified in genome-wide screens) in the lithium-responsive neurological processes. The proposed research is innovative in that it capitalizes on the power of Drosophila genetics to identify and characterize genes that are involved in lithium's actions in the nervous system. The proposed research is significant because it is expected to lead to the recognition of molecules and molecular interactions that are responsible for lithium's actions in the vertebrate nervous system. This would open up new avenues toward a better understanding of the etiology and pathophysiology of BPD, and result in improved therapies for BPD and other disorders of the nervous system.

描述（由申请人提供）：虽然锂显示出显著的情绪稳定特性，并已成为双相情感障碍（BPD）最有效的治疗方法之一，但其对神经系统作用的机制仍不清楚。这个项目的长期目标是在分子和细胞水平上了解锂如何影响神经系统功能。这项提议的目的是确定参与锂反应神经过程的基因，并确定它们在锂治疗作用中的作用。为了实现这些目标，我们将利用果蝇中唯一可用的遗传工具。这些包括神经学突变体Shudderer（Shu），其表型在很大程度上通过治疗浓度的锂给药来挽救。我们的中心假设，这是基于强有力的初步数据，是锂降低神经缺陷的严重程度所造成的上调钙？？？？依赖性磷酸酶钙调磷酸酶，并且它通过抑制先天免疫应答来这样做。这项研究的基本原理是，一旦确定了果蝇中参与锂反应神经过程的基因，并揭示了它们的作用，这些信息应该很容易被翻译到脊椎动物系统中，已知脊椎动物系统使用的信号传导机制与果蝇中的信号传导机制广泛重叠。因此，我们的研究有望为锂的治疗作用提供新的和重要的见解-不仅是关于BPD，而且还有其他神经系统疾病。我们的中心假设将通过追求三个具体目标进行测试：1）确定钙调神经磷酸酶的上调如何导致锂反应性神经缺陷; 2）描述锂对Shu表型的治疗作用的机制; 3）识别其上调或下调模拟锂在神经系统中的作用的新基因。对于第一个目标，特定的细胞类型和发育时间的钙调磷酸酶过表达导致的舒表型将被定义通过遗传操纵钙调磷酸酶活性在空间和时间上的具体方式。对于第二个目标，将利用各种遗传变异来确定先天免疫系统参与锂反应性神经缺陷表现的程度。对于第三个目标，将采用分子定义的突变体和RNAi来确认新基因（来自已在全基因组筛选中鉴定的候选基因）参与锂响应神经过程。这项拟议中的研究是创新的，因为它利用果蝇遗传学的力量来识别和表征参与锂在神经系统中作用的基因。这项拟议中的研究意义重大，因为它有望导致识别负责锂在脊椎动物神经系统中作用的分子和分子相互作用。这将为更好地理解BPD的病因学和病理生理学开辟新的途径，并改善BPD和其他神经系统疾病的治疗方法。