Molecular genetics of thermotaxis

描述（由申请人提供）：我们提出的研究目标是了解果蝇（Drosophila melanogaster）趋热性的分子机制。热趋向性，即向偏好温度的运动，已经在广泛的脊椎动物和无脊椎动物中进行了研究。然而，只有少数基因和蛋白质需要温度识别是已知的。提出这项研究有两个理由。首先，昆虫的热亲和性具有潜在的医学相关性，因为疾病传播媒介（如传播疟疾的冈比亚按蚊）的寻宿主行为似乎涉及温度感觉。因此，识别这种行为所必需的蛋白质可能会导致干扰它的方法。果蝇同源的TRP通道是哺乳动物的热感受器，也具有热趋向性。由于哺乳动物的几种热trps也受到厌恶化学物质的调节，我们提出果蝇的热trps可能是驱蚊剂的靶点。鉴于蚊媒疾病是一个全球性的健康问题，驱蚊剂分子靶点的发现具有医学意义。其次，观察到trp是果蝇和哺乳动物的体温传感器，提出了其他在体温感知中起作用的蛋白质可能是共享的可能性。因此，鉴定果蝇的亲热性基因和蛋白质可能为哺乳动物的热感觉提供新的见解。为了表征热致性和热trps，我们建议使用多学科方法，结合遗传学，生物化学，细胞生物学，分子生物学和电生理学。本研究的具体目的是：1)验证TRP通道（Painless）在成虫的热致性中起作用的假设；2)验证热致性通道（thermoTRPs）是驱蚊剂靶点的假设；3)验证TRPV通道（Nanchung和Inactive）联合作用于幼虫的热致性的假设；4)验证视紫红质在热致性信号通路中的作用的假设。最后一个目的是测试关于视紫红质是直接热传感器的提议，这可能解释了长期已知的现象，即暗噪声和视紫红质的自发激活对温度敏感。这项研究的长期目标是将对果蝇热致变色蛋白的研究成果应用于识别改进的驱虫剂，并测试抑制热致变色行为的药物的功效，这些药物可以应用于医学上重要的双翅目昆虫。公共卫生相关性：拟议的研究涉及鉴定果蝇中对热亲和性和对驱虫剂反应重要的基因和蛋白质。这项拟议研究的一个长期目标是将这些见解应用于果蝇，以确定改进的驱虫剂，并测试抑制热驱动的热致性行为的药物的功效，这种药物可以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.