Regulation of a Pacemaker Neural Output in Drosophila Circadian Rhythms

描述（由申请人提供）：该奖项的一个中心目的是提供培训，从博士后研究员成功过渡到独立的研究员。在建议的指导阶段，李尔博士将获得导师拉维·阿拉达博士和共同导师弗雷德·图雷克博士的技术培训和职业指导。提供这种培训所需的所有设施和设备都可在西北大学。指导阶段还将为其他职业发展活动留出时间，包括教师求职。在独立阶段，Lear博士将使用所接受的培训和以前的专业知识，以执行和指导研究计划中概述的实验。候选人的长期目标是建立一个成功的独立研究计划，研究昼夜节律行为的神经和遗传基础，使用模型系统果蝇。 本文概述的研究计划的目标是利用遗传、分子和生物化学方法阐明昼夜神经输出的调节机制。先前的研究已经证实，假定的离子通道narrowabdominal（na）在果蝇昼夜节律起搏神经元的输出中起作用。然而，我们对na的调控知之甚少，果蝇和哺乳动物对神经输出的昼夜节律调控仍然知之甚少。dunc-79是果蝇中一个新的NA基因突变体，其NA表达水平显著下降，并表现出与NA基因突变体相似的昼夜节律表型。线虫和哺乳动物，初步证据表明，该基因可能是昼夜调节。本提案将研究dunc-79在昼夜节律和NA调节中的作用。本研究的具体目的如下：（1）研究dunc-79（一种假定的NA调节剂）在果蝇昼夜节律中的作用;（2）研究dunc-79调节NA的机制;（3）检验dunc-79受昼夜节律调节的假说。 这一建议与NIGMS阐明行为的神经遗传学的使命高度相关。拟议的研究计划对人类健康也有重大影响。缺陷的昼夜节律与疾病状态相关，包括双相情感障碍和季节性情感障碍。此外，最初在果蝇中鉴定和表征的昼夜节律基因已被证明在包括人类在内的哺乳动物中具有类似的功能。

DESCRIPTION (provided by applicant): A central purpose of this award is to provide training to the grantee for successful transition from postdoctoral fellow to independent investigator. During the mentored phase of the proposal, Dr. Lear will obtain technical training and career guidance from the mentor, Dr. Ravi Allada, and co-mentor, Dr. Fred Turek. All facilities and equipment necessary to provide this training are available at Northwestern University. The mentored phase will also allow time for other career development activities, including the faculty job search. In the independent phase, Dr. Lear will use the training received and previous expertise in order to perform and direct the experiments outlined in the research plan. The long-term of goal of the candidate is to establish a successful independent research program studying the neural and genetic basis of circadian behavior, using the model system Drosophila melanogaster. The goal of the research plan outlined here is to elucidate regulatory mechanisms of circadian neural output, using genetic, molecular, and biochemical approaches. Previous research has demonstrated that putative ion channel narrow abdomen (na) functions in output of Drosophila circadian pacemaker neurons. However, little is known about regulation of na, and the circadian regulation of neural outputs remains poorly understood in both Drosophila and mammals. A novel Drosophila mutant, dunc-79, exhibits a strong decrease in NA expression levels and displays circadian phenotypes similar to those of na mutants, dunc-79 encodes a novel protein with homologs in C. elegans and mammals, and preliminary evidence suggests that this gene may be circadianly regulated. This proposal will examine the role of the dunc-79 in circadian rhythms and NA regulation. The specific aims of this proposal are as follows: (1) to examine the role of dunc-79, a putative NA regulator, in Drosophila circadian rhythms; (2) to examine the mechanism of dunc-79 regulation of NA; (3) to test the hypothesis that dunc-79 is circadianly regulated. This proposal is highly relevant to the mission of NIGMS to elucidate the neurogenetics of behavior. The proposed research plan also has significant implications for human health. Defective circadian rhythms are associated with disease states including bipolar disorder and seasonal affective disorder. Moreover, circadian rhythms genes originally identified and characterized in Drosophila have been shown to have similar function in mammals, including humans.