CLINICAL TRIAL: EFFECT OF GENE VARIANTS ON DOPAMINE RECEPTOR NATRIURETIC RESPONS

临床试验：基因变异对多巴胺受体尿钠反应的影响

• 批准号: 7951502
• 负责人: ROBERT MUNSON CAREY
• 金额: $ 8.97万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7951502
• 关键词: Adenylate Cyclase; Cell model; Clinical Research; Clinical Trials; Complex; Computer Retrieval of Information on Scientific Projects Database; Coupling; Defect; Dopamine D1 Receptor; Dopamine Receptor; Essential Hypertension; Fenoldopam; Funding; GTP-Binding Proteins; Genetic Variation; Grant; Human; Hypertension; Institution; Kidney; Ligands; Natriuresis; Phosphorylation; Protocols documentation; Receptor Activation; Research; Research Personnel; Resources; Serine; Source; Translations; United States National Institutes of Health; Variant; desensitization; prevent; response; saluretic

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. Our research group has discovered a D1 receptor/adenylyl cyclase coupling defect in renal PTCs from subjects with essential hypertension. We have found increased GRK-4 activity in renal PTCs in human essential hypertension due to activating variants of GRK-4, an effect that was reproduced in a transfected cell model. Preventing the translation of GRK-4 normalized the coupling of the D1 receptor to adenylyl cyclase in hypertension. Gene variants of GRK-4 cause a ligand-independent serine-phosphorylation of the D1 receptor, resulting in its uncoupling from the G-protein/effector complex. The desensitization of the D1 receptor in the renal PTC is hypothesized to be the cause of the compromised natriuretic effect of DA that eventually leads to Na+ retention and hypertension. The primary objective of this protocol is to demonstrate that natriuresis engendered by D1-like receptor activation with fenoldopam is blunted in subjects with 3 or more SNPs of GRK-4 compared with responses in subjects with 0-2 SNPs.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 我们的研究小组发现了来自患有基本高血压的受试者的肾脏PTC中的D1受体/腺苷酸环化酶偶联缺陷。 我们已经发现，由于GRK-4的激活变异，在人类本质高血压中肾脏PTC中的GRK-4活性增加，这一作用在转染的细胞模型中得到了再现。 防止GRK-4的翻译使D1受体与高血压中D1受体偶联。 GRK-4的基因变异引起D1受体的非配体丝氨酸磷酸化，从而导致其与G蛋白/效应子复合物的解偶联。 假设D1受体在肾脏PTC中的脱敏是DA最终导致Na+保留和高血压的DA造成的纳地尿作用的原因。 该方案的主要目的是证明，与0-2 SNP的受试者的反应相比，在患有3个或更多SNP的GRK-4 SNP的受试者中，fenoldopam引起的纳特里雷SIS被fenoldopam引起的纳特里氏菌被钝化。