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，但潜在的机制尚不清楚。前列腺素是一种局部作用的脂质激素，来源于必需的膳食脂肪。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，并可能对精子功能有直接影响。然而，它们的确切作用和监管机制一直难以描述。线虫秀丽隐杆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。先前资助期的结果表明，秀丽隐杆线虫卵母细胞可合成多种结构相关的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达受精部位，从而增加

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.