Molecular genetics of thermotaxis

描述（由申请人提供）：我们拟议研究的目标是了解果蝇（Drosophila melanogaster）趋热性的分子机制。趋热性，即朝向优选温度的运动，已经在广泛的脊椎动物和无脊椎动物生物体中进行了研究。然而，只有少数的基因和蛋白质所需的温度歧视是已知的。提出的研究有两个理由。首先，昆虫的趋热性具有潜在的医学相关性，因为疾病传播媒介（如疟疾传播昆虫冈比亚按蚊）的宿主寻找行为似乎涉及温度感觉。因此，鉴定这种行为所必需的蛋白质可能会导致干扰它的方法。果蝇TRP通道的同源物，这是哺乳动物中的温度传感器，也在趋热性中起作用。由于哺乳动物中的几个thermoTRP也受到厌恶性化学物质的调节，我们建议果蝇thermoTRP可能是驱虫剂的目标。驱蚊剂分子靶点的发现具有医学意义，因为蚊子传播的疾病是一个全球性的健康问题。第二，TRP是苍蝇和哺乳动物的热感受器的观察结果提出了其他蛋白质在温度感知中发挥作用的可能性。因此，鉴定果蝇趋热性的基因和蛋白质可能为哺乳动物的温度感觉提供新的见解。为了表征趋热性和thermoTRP，我们建议使用多学科的方法，使用遗传学，生物化学，细胞生物学，分子生物学和电生理学的组合。本提案的具体目的是：1）检验TRP通道（无痛）在成虫趋热性中起作用的假设，2）检验thermoTRP是驱虫剂靶标的假设，3）检验TRPV通道（Nanchung和Inactive）联合作用于幼虫趋热性的假设，以及4）检验视紫红质在趋热性信号通路中起作用的假设。这最后一个目的是测试的建议，视紫红质是直接的温度传感器，这可能是长期已知的现象，即暗噪声和自发激活的视紫红质是温度敏感的。拟议研究的长期目标是应用对果蝇thermoTRP的见解来识别改进的驱虫剂，并测试抑制热驱动的趋热行为的药物的功效，这些药物可应用于医学上重要的双翅目昆虫。公共卫生相关性：拟议的研究涉及确定果蝇中对趋热性和对驱虫剂反应重要的基因和蛋白质。拟议研究的长期目标是应用对果蝇的见解来识别改进的驱虫剂，并测试抑制热驱动趋热行为的药物的功效，这些药物可应用于医学上重要的昆虫，例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.