Male contraception/CatSper1,2 sperm-specific ion channe*

男性避孕/CatSper1,2精子特异性离子通道*

• 批准号: 6848353
• 负责人: DAVID E. CLAPHAM
• 金额: $ 15.18万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-30 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848353
• 关键词: acrosome; calcium; cell line; contraceptives; cooperative study; fertility; fertilization; gene expression; immunocytochemistry; immunoelectron microscopy; laboratory mouse; membrane channels; protein protein interaction; small molecule; sperm; sperm motility; testis; yeast two hybrid system

DESCRIPTION (provided by applicant): The fusion of sperm and egg lead to the combination of the father's and mother's genetic information to create a new individual. In humans, as in all mammals, sperm must reach the egg, penetrate its protective coat, fuse with the oocyte membrane, and deliver its genetic material. Ion channels in the sperm mediate many of these steps, but most of these ion channels are also present in other tissues, including brain and heart. We have identified a class of ion channels, called CatSpers (Cation channel of Sperm) that are in mature sperm but not in any other tissues of the body, including developing organs. CatSpers are six transmembrane-spanning ion channel proteins localized primarily to the tail of mature sperm (Ren et al., 2001). CatSper1, the first of these ion channels to be identified, triggers calcium influx into the principal piece of the sperm tail. Calcium is required for sperm motility, and sperm from mice genetically engineered to lack the functional CatSper1 gene show a significant reduction in motility. Male mice homozygous for null-mutations in the CatSper1 gene are infertile (100%), but otherwise are completely normal. Another related sperm-specific protein, CatSper2, is also localized to its tail. Since these ion channels are only in mature sperm and required for fertility, a specific agent that blocks channel function should prevent fertilization. Experiments are proposed that will enable the expression of these novel genes in heterologous cell lines suitable for large-scale screening for small molecule blockers. This will provide a viable assay for screening for male contraceptive agents.

描述（申请人提供）：精子和卵子的融合导致父亲和母亲的遗传信息结合，创造出一个新的个体。与所有哺乳动物一样，人类的精子必须到达卵子，穿透其保护层，与卵母细胞膜融合，并传递其遗传物质。精子中的离子通道介导许多这些步骤，但大多数这些离子通道也存在于其他组织中，包括大脑和心脏。我们已经确定了一类离子通道，称为 CatSpers（精子阳离子通道），它们存在于成熟精子中，但不存在于身体的任何其他组织中，包括发育中的器官。 CatSpers 是六种跨膜离子通道蛋白，主要定位于成熟精子的尾部（Ren 等，2001）。 CatSper1 是第一个被识别的离子通道，它会触发钙流入精子尾部的主要部分。精子活力需要钙，而经过基因工程改造而缺乏功能性 CatSper1 基因的小鼠的精子表现出活力显着下降。 CatSper1 基因无效突变纯合的雄性小鼠不育 (100%)，但其他方面完全正常。另一种相关的精子特异性蛋白 CatSper2 也位于其尾部。由于这些离子通道仅存在于成熟的精子中并且是生育所必需的，因此阻断通道功能的特定试剂应该可以防止受精。提出的实验将使这些新基因在适合大规模筛选小分子阻断剂的异源细胞系中表达。这将为筛选男性避孕药提供可行的测定方法。