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LKS AND LKUR IN GRANULOSA CELLS

颗粒细胞中的 LKS 和 LKUR

基本信息

批准号：
6625267
负责人：
Lisa C. Freeman
金额：
$ 19.88万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-01 至 2004-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6625267
关键词：
animal tissue cell differentiation cell proliferation cyclic AMP electrophysiology enzyme activity female granulosa cell inhibitor /antagonist potassium channel protein kinase A protein kinase C reproductive system pharmacology tissue /cell culture voltage gated channel

项目摘要

The long-term goals of the research are to increase knowledge about ion channels present in ovarian granulosa cells (GC), and suggest potential roles for ion channels in GC function. The proposed project will focus specifically on the regulatory properties and functional significance of: a slowly activating, non-inactivating delayed rectifier K+ current (IKs), and an utra-rapidly activating delayed rectifier K+ curren (IKur). The major hypotheses to be tested are 1) IKs and IKur are modulated by signal transduction systems implicated in granulosa cell growth and differentiation; 2) IKs, IKur, or both potassium conductances are required for normal granulosa cell maturation. Electrophysiological and cell culture techniques will be used to address these hypotheses experimentally. Biochemical techniques will be used to define the channel proteins that contribute to IKur. Specifically, experiments were designed to: 1) Compare the properties of granulosa cell IKs to those of the cardiac slow delayed rectifier K+ current, and those of the slow K+ currents associated with co-expression of min-K and KvLQT1, the channel proteins that associate to form functional Ks channels; 2) Compare the properties of granulosa cell IKur to those of delayed rectifier K+ currents in other cell types, and delayed rectifier K+ currents associated with expression of the Kv (Shaker subfamily) channel proteins that contribute to IKur; 3) Determine whether or not the inhibitory effects of various K+ channel antagonists on granulosa cell maturation are related to blockade of IKs or IKur. It will be critical not only to define the physiological role(s) of IKs and IKur in GC maturation, but also to compare the pharmacological profiles of the GC currents to those of delayed rectifier currents in other cells. K+ channels have been identified as therapeutic targets in heart, smooth muscle, lymphocytes, and brain (Carmeleit, 1991). GC IKs and IKur may represent either novel targets for assisted reproduction, or potential sites of toxicity for drugs designed to treat arrhythmias, asthma, incontinence, immunosuppression or epilepsy.

这项研究的长期目标是增加对离子的了解，通道存在于卵巢颗粒细胞（GC），并提示可能离子通道在GC功能中的作用。拟议项目将侧重于特别是对调控特性和功能意义的研究缓慢激活、非失活延迟整流钾离子电流 (IKs)和超快速激活的延迟整流钾电流（IKur）. 待检验的主要假设是：1）IKs和IKur是受颗粒细胞信号转导系统的调节生长和分化; 2）IKs、IKur或两者的钾电导是正常颗粒细胞成熟所必需的。电生理细胞培养技术将被用来解决这些假设实验性的生物化学技术将被用来定义通道蛋白，有助于IKur。具体来说，实验 1）比较颗粒细胞IKs的特性，心脏慢延迟整流钾电流的那些，和与min-K和KvLQT 1共表达相关的慢K+电流，结合形成功能性Ks通道的通道蛋白; 2）比较颗粒细胞IKur和延迟排卵颗粒细胞IKur的特性，其他细胞类型的整流钾电流和延迟整流钾电流与Kv（Shaker亚家族）通道表达相关的电流蛋白质，有助于IKur; 3）确定是否有不同钾通道拮抗剂对颗粒细胞抑制作用成熟与IKs或IKur的阻断有关。不仅要确定IKs的生理作用，和IKur在GC成熟中的作用，而且还比较了 GC电流的曲线与延迟整流器电流的曲线，其他细胞。 K+通道已被确定为治疗靶点在心脏、平滑肌、淋巴细胞和脑中（Carmeleit，1991）。 GC IKs和IKur可能代表辅助治疗的新靶点，生殖，或潜在的毒性部位的药物设计，以治疗心律失常、哮喘、失禁、免疫抑制或癫痫。