Molecular genetics of thermotaxis

描述(由申请人提供)：我们提出的研究的目标是了解果蝇黑腹果蝇趋热的分子机制。在许多脊椎动物和无脊椎动物中，已经研究了趋热性，也就是朝向首选温度的运动。然而，只有为数不多的温度辨别所需的基因和蛋白质是已知的。这项拟议的研究有两个理由。首先，昆虫的趋热性具有潜在的医学意义，因为疾病传播媒介，如传播疟疾的冈比亚按蚊，寻找宿主的行为似乎涉及温度感觉。因此，识别对这种行为至关重要的蛋白质可能会导致干扰这种行为的方法。果蝇的色氨酸通道同源物是哺乳动物的温度传感器，也在趋热性中发挥作用。由于哺乳动物中的几个温度TRPs也受到厌恶的化学物质的调节，我们认为果蝇的温度TRPs可能是驱虫剂的靶标。驱蚊剂分子靶标的发现具有医学意义，因为蚊媒疾病是一个世界性的健康问题。第二，观察到在果蝇和哺乳动物中TRP是温度传感器，这增加了其他在温度感觉中起作用的蛋白质可能是共享的可能性。因此，鉴定在果蝇体温趋向性中起作用的基因和蛋白质可能会为哺乳动物的体温感受提供新的见解。为了表征热趋向性和热TRPs，我们建议使用一种多学科的方法，结合遗传学、生物化学、细胞生物学、分子生物学和电生理学。目前建议的具体目标是：1)测试TRP通道(无痛)在成虫趋热中的作用的假设，2)测试热TRPs是驱虫剂靶标的假设，3)测试TRPV通道(南充和非活跃的)联合作用于幼虫趋热的假设，以及4)测试视紫红质在趋热信号通路中功能的假设。最后一个目的是测试视紫红质是直接温度传感器的建议，这可能解释了长期以来已知的现象，即视紫红质的暗噪声和自发激活是温度敏感的。这项拟议研究的长期目标是将这些见解应用到果蝇身上，以确定改进的驱虫剂，并测试可以应用于医学上重要的双翅目昆虫的抑制热驱动趋热行为的药物的有效性。与公共卫生相关：拟议的研究涉及识别对果蝇的趋热性和对驱虫剂的反应至关重要的基因和蛋白质。这项拟议研究的长期目标是将这些见解应用于果蝇，以确定改进的驱虫剂，并测试抑制热驱动趋热行为的药物的有效性，这些药物可以应用于医学上重要的昆虫，如传播疟疾和西尼罗河病毒的昆虫。

DESCRIPTION (provided by applicant): The goal of our proposed research is to understand the molecular mechanisms underlying thermotaxis in the fruitfly, Drosophila melanogaster. Thermotaxis, which is the movement towards a preferred temperature, has been studied in a wide range of vertebrate and invertebrate organisms. However, only a few of the genes and proteins required for temperature discrimination are known. There are two rationales for the proposed research. First, thermotaxis in insects has potential medical relevance, as the host-seeking behaviors of disease spreading vectors, such as the malaria-spreading insect, Anopheles gambiae, appear to involve temperature sensation. Thus, identification of the proteins essential for this behavior may lead to approaches to interfere with it. Drosophila homologs of TRP channels, which are thermosensors in mammals, also function in thermotaxis. Since several thermoTRPs in mammals are also regulated by aversive chemicals, we propose that Drosophila thermoTRPs may be targets for insect repellents. The discovery of the molecular targets for repellents has medical implications, given that mosquito-borne disease is a worldwide health problem. Second, the observations that TRPs are themosensors in flies and mammals raise the possibility that other proteins that function in thermosensation may be shared. Thus, identification of genes and proteins that function in Drosophila thermotaxis may provide new insights into mammalian thermosensation. To characterize thermotaxis and thermoTRPs, we propose to use a multidisciplinary approach, using a combination of genetics, biochemistry, cell biology, molecular biology and electrophysiology. The specific aims of the current proposal are to: 1) test the hypothesis that a TRP channel (Painless) functions in thermotaxis in adult flies, 2) test the hypothesis that thermoTRPs are targets for insect repellents, 3) test the hypothesis that the TRPV channels (Nanchung and Inactive) operate in combination for larval thermotaxis, and 4) test the hypothesis that rhodopsins function in a thermotaxis signaling pathway. This last aim is concerned with testing the proposal that rhodopsins are direct thermosensors, which may account for the long-known phenomenon that dark-noise and spontaneous activation of rhodopsin is temperature sensitive. A long-term goal of the proposed research is to apply the insights on Drosophila thermoTRPs to identify improved insect repellents and to test the efficacies of drugs that inhibit thermally-driven thermotaxis behaviors that could be applied to medically important Diptera. PUBLIC HEALTH RELEVANCE: The proposed research is concerned with identifying the genes and proteins that are important for thermotaxis and the responses to insect repellents, in the fruitfly. A long-term goal of the proposed research is to apply the insights on fruitfly to identify improved insect repellents and to test the efficacies of drugs that inhibit thermally-driven thermotaxis behaviors that could be applied to medically important insects, such as those that spread malaria and West Nile Virus.