Prostaglandins in C. elegans Fertilization

项目摘要 前列腺素作用的分子机制对生殖系统的发育具有相当重要的意义。 生物学家、免疫学家、神经生物学家和肿瘤学家。阿司匹林和其他非甾体抗- 炎性药物（NSAID）特异性抑制前列腺素合成， 癌症预防和可逆转的不孕症。前列腺素是排卵和受精所必需的， 但分子机制还不清楚。老鼠是唯一的遗传系统 目前可用于研究前列腺素在生殖过程中的功能。的目的 应用是确定线虫模型秀丽隐杆线虫可以在多大程度上 用于解决前列腺素生物学中的基本问题。为达致这个目标，我们会 验证卵母细胞合成前列腺素来调节排卵和精子的中心假设 指导支持这一假设的初步数据显示，前列腺素 需要前体、多不饱和脂肪酸（PUFA）和预测的前列腺素脱氢酶 对于这些过程。此外，在缺乏胰岛素的情况下， PUFA。我们的第一个目标是描绘一个前列腺素生物合成途径，在卵母细胞中发挥作用。 为了实现这一目标，我们将在遗传学上表征预测的前列腺素生物合成酶。 和生化水平。我们的第二个目标是确定在多大程度上， NSAIDs影响受精。为了实现这一目标，我们将研究的影响， NSAID对精子活力和体内排卵的影响。我们的最终目标是识别PUFA衍生的信号 由卵母细胞合成。遗传学和液相色谱的结合， 电喷雾电离串联质谱法将用于实现这一目标。我们预计 完成拟议的目标将建立C。线虫的性腺是第一个简单的， 用于发现生殖过程中前列腺素作用的分子机制的易处理模型。 这些研究应该会导致对基因的全面描述， 前列腺素的合成和功能，其中任何一个都可以编码新的药物靶点。的作用 哺乳动物受精过程中的前列腺素可能是保守的，前列腺素支持这一观点。 缺陷小鼠无论如何，对C。秀丽线虫的性腺 发现人类不育、避孕和癌症的分子机制的潜力。

Project Summary The molecular mechanisms of prostaglandin action are of considerable importance to reproductive biologists, immunologists, neurobiologists, and oncologists. Aspirin and other non-steroidal anti- inflammatory drugs (NSAIDs) specifically inhibit prostaglandin synthesis and are associated with cancer prevention and reversible infertility. Prostaglandins are essential for ovulation and fertilization, but the molecular mechanisms are not well understood. The mouse is the only genetic system currently available to study prostaglandin functions during reproduction. The objective of this application is to determine the extent to which the nematode model Caenorhabditis elegans can be used to address fundamental questions in prostaglandin biology. To achieve this objective, we will test the central hypothesis that oocytes synthesize prostaglandins to regulate ovulation and sperm guidance. Support for this hypothesis comes from preliminary data showing that prostaglandin precursors, polyunsaturated fatty acids (PUFAs), and predicted prostaglandin synthases are required for these processes. In addition, prostaglandins can regulate sperm motility in the absence of PUFAs. Our first aim is to delineate a prostaglandin biosynthesis pathway that functions in oocytes. To achieve this aim, we will characterize predicted prostaglandin biosynthesis enzymes at the genetic and biochemical levels. Our second aim is to determine the extent to which prostaglandins and NSAIDs influence fertilization. To achieve this aim, we will examine the effects of prostaglandins and NSAIDs on sperm motility and ovulation in vivo. Our final aim is to identify the PUFA-derived signals synthesized by oocytes. A combination of genetics and liquid chromatography coupled to electrospray ionization tandem mass spectrometry will be used to achieve this aim. We expect that completing the proposed aims will establish the C. elegans gonad as the first simple, genetically tractable model for discovering molecular mechanisms of prostaglandin action during reproduction. These studies should lead to a comprehensive delineation of genes that are required for prostaglandin synthesis and function, any of which could encode new drug targets. The role of prostaglandins in fertilization could be conserved in mammals, an idea supported by prostaglandin deficient mice. Regardless, basic research on prostaglandins in the C. elegans gonad has the potential for discovering molecular mechanisms of human infertility, contraception, and cancer.