Prostaglandins in C. elegans Fertilization

描述(由申请人提供)：饮食成分和环境暴露会影响配子功能和生育能力，但其潜在机制尚不清楚。前列腺素是一种局部作用的脂类激素，来源于必需的饮食脂肪。在人类卵巢中，前列腺素被认为促进了对受精至关重要的多个过程，并可能对精子功能产生直接影响。然而，它们的确切作用和监管机制一直很难描述。线虫线虫是研究前列腺素在生殖过程中的一个强大而简单的模型。前一个资助期的结果表明，线虫卵母细胞合成了多种结构上相关的F系列前列腺素，包括PGF1和PGF2立体异构体。这些前列腺素共同和部分冗余地引导精子到受精部位，从而增加 生殖产量。这项建议提供了强有力的初步证据，支持这一模型，即由纤毛感觉神经元感知的食物来源和其他环境线索是卵巢前列腺素合成的关键调节因素。已知这些外部信号调节头部ASI感觉神经元中名为DAF-7的转化生长因子β(TGF-β)同系物的表达。这项提议的目的是描述女性食物感觉神经元调节精子功能的机制。中心假说是ASI感觉神经元分泌DAF-7/TGF-β促进卵母细胞前列腺素的合成，后者通过多个G蛋白偶联受体(GPCRs)作用于刺激精子引导。目的1研究女性感觉神经元调节精子活力的机制。其工作假设是，成体感觉神经元分泌DAF-7/转化生长因子-β，启动神经内分泌信号转导机制，触发卵母细胞前列腺素合成。目的2描述精子传递前列腺素信号的机制。工作假设是卵母细胞F系列前列腺素通过GQ上游的多个SRB类GPCRs起作用。这些研究可能揭示，食物来源的线索通过控制精子运动的保守荷尔蒙网络从女性大脑中的感觉神经元传递到生殖道。破坏这些女性神经内分泌机制，无论是通过基因突变、饮食变化或环境暴露，都可能损害精子功能。此外，这一结果可能会揭示前列腺素的新功能和调节机制。神经元到精子信号的异常可能会导致人类和家畜的不孕。

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.