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：
8258310
负责人：
TOSHIHIRO KITAMOTO
金额：
$ 33.41万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258310
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. PUBLIC HEALTH RELEVANCE: The proposed studies aim at understanding the evolutionarily conserved neurological processes that are affected by lithium. This research is of high relevance to public health because lithium is an effective drug for the treatment of mood disorders, as well as potentially being useful for the treatment or prevention of brain damage. Thus, the findings are expected to contribute to significant future improvements in human health.

描述（由申请人提供）：尽管锂显示出显着的情绪稳定的特性，并已成为双相情感障碍（BPD）最有效的疗法之一，但其对神经系统作用的机制仍不清楚。该项目的长期目标是理解分子和细胞水平，锂如何影响神经系统功能。该提案的目标是确定与锂反应性神经过程有关的基因，并确定其在锂的治疗作用中的作用。为了实现这些目标，我们将利用在果蝇果蝇中独特可用的遗传工具。其中包括神经系统突变体颤抖（SHU），其表型在很大程度上是由锂给药以治疗浓度挽救的。我们的中心假设基于强有力的初步数据，是锂可以降低由Ca2上调的神经系统缺陷的严重程度？拟议的研究的理由是，一旦已经确定了果蝇中锂反应性神经过程的基因，并且已经揭示了它们的作用，则应轻松地将这些信息转化为脊椎动物系统，该信息已知使用与Drosophilla中广泛重叠的信号机制。因此，我们的研究有望提供对锂的治疗作用的新颖和重要见解，不仅尊重BPD，而且还尊重其他神经系统疾病。我们的中心假设将通过追求三个具体目的来检验：1）确定钙调神经酶的上调如何导致锂反应性神经缺陷； 2）描述负责锂对SHU表型的治疗作用的机制； 3）确定上调或下调模仿锂在神经系统中的作用的新型基因。对于第一个目的，将通过以空间和时间上特定的方式遗传操纵钙调神经素活性来定义导致SHU表型的钙调神经蛋白过表达的特定细胞类型和发育时机。为了第二个目标，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系统缺陷的表现的程度。为了第三个目标，将使用分子定义的突变体和RNAi来确认在锂反应性神经过程中的新基因的参与（来自在全基因组筛查中已鉴定出的候选者）。拟议的研究具有创新性，因为它利用了果蝇遗传学的能力来识别和表征与锂在神经系统中锂作用有关的基因。拟议的研究很重要，因为预计它将导致识别分子和分子相互作用，这些分子和分子相互作用负责锂在脊椎动物神经系统中的作用。这将为对BPD的病因和病理生理学的更好理解开辟新的途径，并改善BPD和神经系统其他疾病的疗法。公共卫生相关性：拟议的研究旨在理解受锂影响的进化保守的神经过程。这项研究与公共卫生具有很高的相关性，因为锂是一种治疗情绪障碍的有效药物，并且有可能对治疗或预防脑损伤有用。因此，这些发现预计将有助于人类健康的重大改善。