Prostaglandins in C. elegans Fertilization

项目摘要 前列腺素作用的分子机制对生殖相当重要。 生物学家、免疫学家、神经生物学家和肿瘤学家。阿司匹林和其他非类固醇抗精神病药物 炎症药物(NSAIDs)特异性地抑制前列腺素合成，并与 癌症预防和可逆性不孕。前列腺素对排卵和受精是必不可少的， 但其分子机制还不是很清楚。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作用。这样做的目的是 应用是确定线虫模型秀丽线虫在多大程度上 用于解决前列腺素生物学中的基本问题。为了达到这一目标，我们将 检验卵母细胞合成前列腺素以调节排卵和精子的中心假说 指导。支持这一假设的初步数据显示，前列腺素 前体、多不饱和脂肪酸(PUFAs)和预测的前列腺素合成酶是必需的 对于这些过程。此外，前列腺素还可以在缺乏精子的情况下调节精子活力 多不饱和脂肪酸。我们的第一个目标是描述在卵母细胞中发挥作用的前列腺素生物合成途径。 为了实现这一目标，我们将在基因水平上对预测的前列腺素生物合成酶进行表征。 和生化水平。我们的第二个目标是确定前列腺素和 非甾体抗炎药影响受精。为了实现这一目标，我们将研究前列腺素和 非甾体抗炎药对精子活力和体内排卵的影响。我们的最终目标是识别PUFA派生的信号 由卵母细胞合成。遗传学和高效液相色谱结合在一起 电喷雾电离串联质谱仪将被用来实现这一目标。我们期待着 完成拟议的目标将使线虫性腺成为第一个简单的、从基因上 用于发现前列腺素在生殖过程中作用的分子机制的易处理模型。 这些研究应该导致全面描绘出 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 前列腺素在哺乳动物受精过程中是保守的，这一观点得到前列腺素的支持 有缺陷的小鼠。无论如何，对线虫性腺中前列腺素的基础研究 有可能发现人类不孕不育、避孕和癌症的分子机制。项目叙事 前列腺素是对人类生殖、免疫和心血管起关键作用的脂质信号。 功能。卵巢前列腺素的基础研究有可能发现分子 癌症、不孕症和避孕的机制。这项提案的目标是确定 秀丽隐杆线虫模型系统在多大程度上可以用来阐明分子 前列腺素在生殖过程中的作用机制。

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. Project Narrative Prostaglandins are lipid signals that are critical for human reproduction, immunity, and cardiovascular functions. Basic research on prostaglandins in the ovary has the potential for discovering molecular mechanisms of cancer, infertility, and contraception. The objective of this proposal is to determine the extent to which the model system Caenorhabditis elegans can be used to elucidate the molecular mechanisms of prostaglandin action during reproduction.