Actions of Seminal Proteins in Mated Drosophila Females

描述（由申请人提供）：在交配的雌性哺乳动物和昆虫体内，精液蛋白质引起对生育力重要的生化和生理作用。尽管它们很重要，但这些蛋白质的功能还不清楚。我们使用果蝇的“Acp”精液蛋白作为模型来研究精液蛋白影响雌性的机制。Acps属于生物化学类，在动物中是保守的，并在动物中调节几种类似的生殖现象。因此，我们利用果蝇遗传学来剖析精液蛋白质功能，有助于了解人类生育能力和疾病昆虫媒介的控制。通过对40多个Acps的基因测试和对其功能的分子测试，我们已经确定了调节生殖过程中特定步骤的单个Acps。我们已经表明，他们的行动需要分子或生理串扰之间的男性衍生的Acps和分子或条件的女性。为了精确地定义特定的Acps如何与女性一起工作，以介导其影响，我们建议集中在两个步骤，迅速发生在果蝇交配后。具体来说，我们将解剖的Acp ovulin在触发排卵的作用，通过确定其作用的网站，其处理的作用，其受体的身份，以及是否ovulin介导肌肉收缩和生物胺章鱼胺的行为。我们将解剖的方式，其中精液蛋白Acp36DE促进进入存储的精子，通过确定其活性区域，其受体，以及它是否触发囊泡释放，并通过特定的女性生殖道蛋白的行为，造成女性的生殖道构象变化。最后，我们将定义如何组成的男性和女性衍生的组件的蛋白水解途径的过程中交配的女性排卵。相关性：果蝇（Drosophila）的精液蛋白质与人类和其他动物的精液蛋白质类型相似，它们引起的生殖效应在生物体中也是类似的。这使我们能够利用果蝇快速而异常强大的遗传学来快速准确地确定精液蛋白如何促进生殖。由于动物之间的精液蛋白质作用的相似性，我们的研究结果将提供有用的信息来解释和解决某些人类不育的原因，并将有助于设计方法来控制将疾病传播给人类的昆虫的传播。公共卫生相关性：精液蛋白对所有试验动物（包括人类）的生育能力都很重要。在强大的模型系统果蝇中鉴定了一套精液蛋白质，并表明它们调节生殖途径中的特定步骤，我们将剖析这些蛋白质如何与雌性细胞和我们最近发现的分子“对话”中的蛋白质一起工作。由于精液蛋白在动物中的类似作用，我们的研究结果将有助于了解人类的某些不孕症，以及控制人类疾病昆虫载体繁殖的方法。

DESCRIPTION (provided by applicant): Within the bodies of mated female mammals and insects, seminal proteins cause biochemical and physiological effects that are important for fertility. Despite their importance, the functions of these proteins are not well understood. We use Drosophila's "Acp" seminal proteins as a model to investigate the mechanisms by which seminal proteins affect females. Acps fall into biochemical classes that are conserved across animals and regulate several analogous reproductive phenomena across animals. Thus, our use of Drosophila genetics to dissect seminal protein function informs the understanding of human fertility and the control of insect vectors of disease. Through genetic tests of over 40 Acps and molecular tests of their function, we have identified individual Acps that regulate specific steps in reproductive processes. We have shown that their action requires molecular or physiological crosstalk between male-derived Acps and molecules or conditions in females. To define precisely how specific Acps work together with the female to mediate their effects, we propose to focus on two steps that occur rapidly after mating in Drosophila. Specifically, we will dissect the role of the Acp ovulin in triggering ovulation by determining its site of action, the role of its processing, the identity of its receptor, and whether ovulin mediates muscle contractions and acts with the biogenic amine octopamine. We will dissect the way in which the seminal protein Acp36DE promotes the entry of sperm into storage by determining its active regions, its receptor, and whether it triggers vesicle release and acts through particular female reproductive tract proteins to cause conformational changes in the female's reproductive tract. Finally, we will define how a proteolytic pathway composed of male- and female-derived components processes ovulin within mated females. Relevance: The seminal proteins of the fruit fly Drosophila are similar in type to those found in people and other animals, and they cause reproductive effects that are analogous across organisms. This allows us to take advantage of the rapid and unusually powerful genetics of Drosophila to quickly and precisely determine how seminal proteins work to facilitate reproduction. Because of the parallels in seminal protein actions across animals, our results will provide information useful to interpret and address the causes of certain human infertilities, and will help to design methods to control the spread of insects that transmit diseases to people. PUBLIC HEALTH RELEVANCE: Seminal proteins are important for fertility in all animals tested, including humans. Having identified the suite of seminal proteins in the powerful model system Drosophila and shown that they regulate specific steps in reproductive pathways, we will dissect how these proteins work together with female cells and proteins in the molecular "dialogues" that we have recently discovered. Because of analogous actions of seminal proteins across animals, our results will inform understanding of certain infertilities in humans, and methods to control the reproduction of insect vectors of human disease.