Role of Calcineurin Isoforms in Renal Regulation of Blood Pressure

钙调神经磷酸酶亚型在肾脏血压调节中的作用

• 批准号: 9789265
• 负责人: Clintoria Richards Williams
• 金额: $ 17.35万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789265
• 关键词: Address; American; Animal Model; Antihypertensive Agents; Biology; Blood Pressure; Calcineurin; Calcineurin inhibitor; Calcium; Catalytic Domain; Cell Line; Cell model; Cells; Chronic Kidney Failure; Clinical; Core Facility; Data; Development; Distal convoluted renal tubule structure; Equilibrium; Family; Future; Goals; Grant; Hypertension; Impairment; Investigation; Kidney; Knowledge; Literature; LoxP-flanked allele; Mediating; Modeling; Molecular and Cellular Biology; Mus; Outcome; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Protein Isoforms; Proteins; Publishing; Regulation; Renal function; Renal tubule structure; Research; Resources; Role; SLC12A3 gene; Salivary Glands; Signal Pathway; Signal Transduction; Skin; Sodium; Sodium Chloride; Tacrolimus; Techniques; Therapeutic immunosuppression; Threonine; Transgenic Mice; Universities; Up-Regulation; Water; Work; blood pressure regulation; embryonic stem cell; in vitro Model; in vivo; inhibitor/antagonist; innovation; loss of function; mouse model; new therapeutic target; next generation; novel; tool

PROJECT SUMMARY: Approximately 31 million Americans suffer from Chronic Kidney Disease, which is characterized by a progressive decline in kidney function. One of the major contributing factors to Chronic Kidney Disease is high blood pressure or hypertension. Despite several classes of anti-hypertensive drugs, blood pressure remains uncontrolled in more than half of patients. This underscores the need for new drug targets. A feature of uncontrolled blood pressure is dysregulated renal sodium handling. Sodium handling by the kidney is the cornerstone of whole body salt and water balance, and subsequent blood pressure homeostasis. Intracellular mechanisms that regulate renal sodium transporter expression and/or activity offer a new direction for the next generation of blood pressure therapies. By integrating cellular and molecular biology with animal models, our long-term research objective is to identify and exploit signaling pathways that regulate renal sodium transporters and subsequently sodium handling and blood pressure. Calcineurin (CnA) is a new player in the regulation of renal sodium handling and has been identified to be involved in hypertension. Furthermore, clinical and experimental data support a role for CnA in regulation of renal sodium transporters and blood pressure. Consistent with the literature, preliminary studies show that CnA inhibition with tacrolimus (general inhibitor) stimulates the upregulation of the renal sodium chloride cotransporter (NCC). However, understanding of the underlying mechanisms of NCC regulation, renal sodium handling and blood pressure control are limited by a gap in knowledge regarding the specific role of each renal CnA isoform (CnAα and CnAβ). This R21 grant will delineate the contribution of each CnA isoform to blood pressure regulation. To this end, we take advantage of innovative transgenic mouse models and cell lines. The outcomes of this R21 grant will enhance our knowledge of the specific mechanisms by which CnA isoforms regulate blood pressure as well as inform the development of anti-hypertensive and immunosuppressive therapies.

项目摘要： 大约有3100万美国人来自慢性肾脏疾病，其特征是 肾功能的逐步下降。 血压或高血压。 一半以上的患者强调了对新药的需求 不受控制的血压是失调的肾脏钠处理。 全身盐和水平衡的基石 调节肾脏钠转运蛋白表达和/或活动的机制为下一个提供了新的方向 血压疗法产生。 通过将细胞和分子生物学与动物模型相结合，我们的长期研究目标是 识别和利用调节肾脏钠转运蛋白和随后钠的信号通路 处理和血压。 已经涉及高血压。 用于调节肾脏钠转运蛋白和血压的CNA。 初步研究表明，克莫司（一般抑制剂）抑制CNA刺激的上调 但是，肾氯化钠共晶（NCC）。 调节，肾脏钠处理和血压控制受到有关您的知识的差距的限制 每个肾脏CNA同工型（CNAα和CNAβ）的特定作用。 R21赠款将描述每个CNA同工型对血压调节的贡献 最后，我们利用创新的转基因小鼠模型和细胞线。 将增强我们对CNA同工型调节血液压力的特定机制的了解 并告知抗高血压和免疫性疗法的发展。