Studies of genes involved in the lithium responsive neurological processes

描述(申请人提供)：尽管锂显示出显著的稳定情绪的特性，并已成为治疗双相情感障碍(BPD)最有效的疗法之一，但其对神经系统作用的潜在机制仍不清楚。该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。这项建议的目标是识别与锂反应神经过程有关的基因，并确定它们在锂的治疗作用中的作用。为了实现这些目标，我们将利用果蝇黑腹果蝇特有的遗传工具。其中包括一种神经突变Shudder(Shu)，其表型在很大程度上可以通过给予治疗浓度的锂来挽救。我们的中心假设基于强大的初步数据，即锂通过抑制先天免疫反应来降低钙依赖的磷酸酶钙调神经磷酸酶上调引起的神经缺陷的严重程度。这项拟议研究的基本原理是，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，众所周知，脊椎动物系统使用的信号机制与果蝇的信号机制广泛重叠。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-不仅涉及BPD，而且还涉及其他神经疾病。我们的中心假说将通过追求三个具体目标来检验：1)确定钙调神经磷酸酶上调如何导致锂反应的神经缺陷；2)描绘锂对Shu表型的治疗作用的机制；以及3)识别其上调或下调模仿锂在神经系统中的作用的新基因。对于第一个目标，导致Shu表型的钙调神经磷酸酶过表达的特定细胞类型和发育时间将通过以空间和时间特定的方式通过遗传操作钙调神经磷酸酶活性来定义。对于第二个目标，将利用各种遗传变异来确定先天性免疫系统在多大程度上参与了锂反应神经缺陷的表现。对于第三个目标，将使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确定的候选基因)参与锂反应的神经过程。这项拟议的研究具有创新性，因为它利用了果蝇遗传学的力量来识别和表征与锂在神经系统中的作用有关的基因。这项拟议的研究意义重大，因为它有望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。这将为更好地了解BPD的病因和病理生理学开辟新的途径，并导致BPD和其他神经系统疾病的改进治疗。与公共健康相关：拟议的研究旨在了解锂影响的进化保守的神经过程。这项研究与公共健康高度相关，因为锂是治疗情绪障碍的有效药物，也可能对治疗或预防脑损伤有用。因此，这些发现有望为未来人类健康的显著改善做出贡献。

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.