MECHANISMS UNDERLYING NEPHROGENIC DIABETES INSIPIDUS

肾性尿崩症的潜在机制

基本信息

批准号：
3462629
负责人：
ISAAC TEITELBAUM
金额：
$ 8.73万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-08-01 至 1992-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3462629
关键词：
adenylate cyclase cyclic AMP diabetes insipidus diabetic nephropathy fatty acid biosynthesis forskolin kidney metabolism laboratory mouse laboratory rat lithium nephrogenic diabetes insipidus pertussis toxin prostaglandin E tetracyclines vasopressins

项目摘要

The objective of this proposal is to examine the biochemical mechanisms of renal resistance to vasopressin (AVP) in two settings associated with nephrogenic diabetes insipidus (NDI): administration of pharmacologic agents (lithium and demeclocycline) that are known to cause a renal concentrating defect and congenital NDI. The system in which studies will be performed is a primary culture of inner medullary collecting tubule cells that responds specifically to AVP by forming the intermediate effector of the hormone's action, cAMP, in a dose dependent manner. Vasopressin-stimulated cAMP formation will be determined in the presence and absence of phosphodiesterase inhibition. Prostaglandin E2 production in these settings will be measured and the effect of prostaglandin synthesis inhibitors on cAMP production will be assessed. The site of the receptor-adenylate cyclase complex at which any changes occur will be defined. A binding assay will examine receptor function and forskolin will be employed to directly stimulate the catalytic unit. Studies directed at assessing whether a guanine nucleotide binding regulatory subunit defect is operant will employ agents (e.g. cholera toxin, pertussis toxin) known to stimulate at this site. In conjunction with these latter studies an adenylate cyclase complementation assay employing the cyc- mutant of murine S49 lymphoma cells will be performed. These studies will significantly enhance our understanding of the biochemical mechanisms that underly commonly encountered AVP resistant states characterized clinically by polyuria, polydipsia and impaired urinary concentration.

该提议的目的是检查在两个设置中对加压素（AVP）的肾耐药性肾原性糖尿病（NDI）：药物给药已知会引起肾脏集中缺陷和先天性NDI。研究的系统进行内部髓质收集小管的主要培养通过形成中间体来专门响应AVP的单元激素作用的效果以剂量依赖性的方式。血管加压素刺激的营地形成将在存在下确定和缺乏磷酸二酯酶抑制。前列腺素E2生产在这些环境中，将测量和前列腺素的影响将评估营地生产的合成抑制剂。该地点任何发生任何变化的受体 - 腺苷酸环化酶复合物将是定义。结合测定将检查受体功能，福斯科林将被用来直接刺激催化单元。研究指向评估鸟嘌呤核苷酸结合调节亚基缺陷是否是操作者将雇用已知的代理商（例如霍乱毒素，百日咳毒素）在此站点刺激。结合这些后者研究腺苷酸环化合酶互补测定法使用鼠的环形突变体将进行S49淋巴瘤细胞。这些研究将大大增强我们对基础生化机制的理解通常遇到的抗AVP态在临床上以多尿，多次毒和尿液浓度受损。