Prostaglandins in C. elegans Fertilization

描述（由申请人提供）：饮食成分和环境暴露可影响配子功能和生育力，但对潜在机制知之甚少。前列腺素是源自必需膳食脂肪的局部作用脂质激素。在人类卵巢中，芦荟素被认为促进受精的多个关键过程，并可能对精子功能产生直接影响。然而，它们的确切作用和调节机制一直难以界定。线虫C. elegans是一个强大的，但简单的模型，以研究生殖中的异莲心素。上一个资助期的结果表明，C。线虫卵母细胞合成多种结构上相关的F-系列异黄酮，包括PGF 1 <$和PGF 2 <$立体异构体。这些前列腺素共同和部分冗余地发挥作用，将精子引导到受精部位，从而增加精子的受精率。 生殖产出强有力的初步证据提供了支持的模型，食物来源的和其他环境的线索所感知的纤毛感觉神经元是卵巢前列腺素合成的关键调节。已知这些外部线索调节头部ASI感觉神经元中称为β-7的转化生长因子β（TGF-β）同系物的表达。本研究的目的是阐明雌性食物感受神经元调节精子功能的机制。中心假设是ASI感觉神经元分泌β-7/TGF-β来促进卵母细胞胰蛋白酶的合成，其通过多个G蛋白偶联受体（GPCR）起作用以刺激精子引导。目的1拟阐明女性感觉神经元调节精子运动的机制。工作假设是成年感觉神经元分泌β-7/TGF-β启动神经内分泌信号转导机制，触发卵母细胞中的前列腺素合成。目的2提出描绘精子传导前列腺素信号的机制。工作假设是卵母细胞F-系列胰头素通过Gq上游的多个SRB类GPCR起作用。这些研究可能揭示，食物来源的线索从女性大脑中的感觉神经元通过控制精子运动的保守激素网络传递到生殖道。通过基因突变、饮食改变或环境暴露破坏这些女性神经内分泌机制，可能会损害精子功能。此外，这些结果可能会揭示新的前列腺素功能和调节机制。异常的神经元精子信号可能导致人类和牲畜的不育。

DESCRIPTION (provided by applicant): Dietary components and environmental exposures can impact gamete function and fertility, but the underlying mechanisms are poorly understood. Prostaglandins are locally acting lipid hormones derived from essential dietary fats. In the human ovary, prostaglandins are thought to promote multiple processes critical for fertilization and may have a direct effect on sperm function. Their precise roles and regulatory mechanisms have been difficult to delineate, however. The nematode C. elegans is a powerful, yet simple model to investigate prostaglandins in reproduction. Results from the previous funding period have shown that C. elegans oocytes synthesize multiple structurally related F-series prostaglandins, including PGF1¿ and PGF2¿ stereoisomers. These prostaglandins function collectively and partially redundantly to guide sperm to the fertilization site, thereby increasing reproductive output. Strong preliminary evidence provided in this proposal supports the model that food-derived and other environmental cues perceived by ciliated sensory neurons are key regulators of ovarian prostaglandin synthesis. These external cues are known to modulate expression of a transforming growth factor beta (TGF-¿) homolog called DAF-7 in head ASI sensory neurons. The objective of this proposal is to delineate the mechanism by which female food-sensing neurons regulate sperm function. The central hypothesis is that ASI sensory neurons secrete DAF-7/TGF-¿ to promote the synthesis of oocyte prostaglandins, which act via multiple G protein-coupled receptors (GPCRs) to stimulate sperm guidance. Aim 1 proposes to delineate a mechanism by which female sensory neurons regulate sperm motility. The working hypothesis is that adult sensory neurons secrete DAF-7/TGF-¿ to initiate a neuroendocrine signal transduction mechanism triggering prostaglandin synthesis in oocytes. Aim 2 proposes to delineate the mechanism by which sperm transduce prostaglandin signals. The working hypothesis is that oocyte F-series prostaglandins act via multiple SRB class GPCRs upstream of Gq. These studies may reveal that food-derived cues are transmitted from sensory neurons in the female brain to the reproductive tract through conserved hormone networks that control sperm motility. Disrupting these female neuroendocrine mechanisms, either through genetic mutation, dietary changes, or environmental exposures, could impair sperm function. In addition, the results are likely to uncover new prostaglandin functions and regulatory mechanisms. Abnormal neuron to sperm signaling could contribute to infertility in humans and livestock.