GROUP VIA PHOSPHOLIPASE A2 AND SPERM WITH IMPAIRED MOTILITY/REDUCED FERTILITY

通过磷脂酶 A2 和活力受损/生育力降低的精子进行分组

• 批准号: 7355233
• 负责人: S BAO
• 金额: $ 0.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355233
• 关键词: GROUP; VIA; PHOSPHOLIPASE; A2; SPERM

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Group VIA Phospholipase A2 (iPLA2B) is the first recognized cytosolic Ca2+-independent PLA2 and has been proposed to participate in arachidonic acid (20:4) incorporation into glycerophosphocholine lipids, cell proliferation, exocytosis, apoptosis, and other processes. To study iPLA2B functions, we disrupted its gene by homologous recombination to generate mice that do not express iPLA2B. Heterozygous iPLA2B+/- breeding pairs yield a Mendelian 1:2:1 ratio of iPLA2B+/+, iPLA2B+/-, and iPLA2B-/- pups and a 1:1 male:female gender distribution of iPLA2B-/- pups. Several tissues of wild-type mice express iPLA2B mRNA, immunoreactive protein, and activity, and testes express the highest levels. Testes or other tissues of iPLA2B-/- mice express no iPLA2B mRNA or protein, but iPLA2B-/- testes are not deficient in 20:4-containing glycerophosphocholine lipids, indicating that iPLA2B does not play an obligatory role in formation of such lipids in that tissue. Spermatozoa from iPLA2B/- mice have reduced motility and impaired ability to fertilize mouse oocytes in vitro and in vivo, and inhibiting iPLA2B with a bromoenol lactone suicide substrate reduces motility of wild-type spermatozoa in a time- and concentration-dependent manner. Mating iPLA2B-/- male mice with iPLA2B+/+, iPLA2B+/-, or iPLA2B-/- female mice yields only about 7% of the number of pups produced by mating pairs with an iPLA2B+/+ or iPLA2B+/- male, but iPLA2B-/- female mice have nearly normal fertility. These findings indicate that iPLA2B plays an important functional role in spermatozoa, suggest a target for developing male contraceptive drugs, and complement reports that disruption of the Group IVA PLA2 (cPLA2B) gene impairs female reproductive ability.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。VIA族磷脂酶A2（iPLA 2B）是第一种公认的胞质Ca 2+非依赖性PLA 2，并已被提出参与花生四烯酸（20：4）掺入甘油磷酸胆碱脂质、细胞增殖、胞吐、凋亡和其他过程。为了研究iPLA 2B功能，我们通过同源重组破坏其基因以产生不表达iPLA 2B的小鼠。杂合iPLA 2B +/-育种对产生孟德尔1：2：1比率的iPLA 2B +/+、iPLA 2B +/-和iPLA 2B-/-幼仔以及1：1雄性：雌性性别分布的iPLA 2B-/-幼仔。野生型小鼠的几种组织表达iPLA 2B mRNA、免疫反应蛋白和活性，睾丸表达水平最高。iPLA 2B-/-小鼠的睾丸或其他组织不表达iPLA 2B mRNA或蛋白质，但iPLA 2B-/-睾丸不缺乏含20：4的甘油磷酸胆碱脂质，表明iPLA 2B在该组织中形成此类脂质中不起强制性作用。来自iPLA 2B/-小鼠的精子在体外和体内具有降低的运动性和受损的使小鼠卵母细胞受精的能力，并且用溴烯醇内酯自杀底物抑制iPLA 2B以时间和浓度依赖性方式降低野生型精子的运动性。将iPLA 2B-/-雄性小鼠与iPLA 2B +/+、iPLA 2B +/-或iPLA 2B-/-雌性小鼠交配产生的幼崽数量仅为与iPLA 2B +/+或iPLA 2B +/-雄性小鼠交配产生的幼崽数量的约7%，但iPLA 2B-/-雌性小鼠具有几乎正常的生育力。这些研究结果表明，iPLA 2B在精子中起着重要的功能作用，建议开发男性避孕药物的目标，并补充了IVA组PLA 2（cPLA 2B）基因破坏损害女性生殖能力的报道。