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: 10089531
• 负责人: Clintoria Richards Williams
• 金额: $ 4.29万
• 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/10089531
• 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.

项目概要： 大约有3100万美国人患有慢性肾病，其特征是 肾功能逐渐下降慢性肾脏病的主要原因之一是高 血压或高血压。尽管有几类抗高血压药物， 超过一半的患者未得到控制。这就需要寻找新的药物靶点。的特征 不受控制的血压是肾钠处理失调。肾脏对钠的处理是 它是全身盐和水平衡的基石，随后是血压稳态。细胞内 调节肾钠转运蛋白表达和/或活性的机制为下一步研究提供了新的方向。 血压治疗的一代。 通过整合细胞和分子生物学与动物模型，我们的长期研究目标是 鉴定和利用调节肾钠转运蛋白和随后的钠的信号通路 处理和血压。钙调神经磷酸酶（CnA）是调节肾钠处理的新参与者， 已被证实与高血压有关。此外，临床和实验数据支持的作用 CnA在调节肾钠转运蛋白和血压中的作用。与文献一致， 初步研究表明，用他克莫司（一般抑制剂）抑制CnA可刺激 肾脏氯化钠协同转运蛋白（NCC）。然而，对NCC潜在机制的理解 调节、肾钠处理和血压控制受到关于以下方面的知识空白的限制： 每种肾脏CnA亚型（CnAα和CnAβ）的特定作用。 这项R21资助将描述每个CnA亚型对血压调节的贡献。本 最后，我们利用创新的转基因小鼠模型和细胞系。本次R21赠款的结果 将增强我们对CnA亚型调节血压的具体机制的认识， 并为抗高血压和免疫抑制疗法的发展提供信息。