Novel Protein Kinase GI Substrates in Cardiac Remodeling and Blood Pressure Control

心脏重塑和血压控制中的新型蛋白激酶 GI 底物

• 批准号: 9080069
• 负责人: Robert Morris Blanton
• 金额: $ 42万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9080069
• 关键词: Address; Adult; Adverse effects; Arteries; Binding; Blood; Blood Pressure; Blood Vessels; Brain natriuretic peptide; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cessation of life; Clinical; Clinical Trials; Cyclic GMP-Dependent Protein Kinases; Data; Drug Targeting; Heart; Heart failure; Human; Hypertension; Hypotension; In Vitro; Investigation; Knockout Mice; Knowledge; Laboratories; Luciferases; MAPK8 gene; Mediating; Mus; Mutation; Myocardium; Myography; Pathologic; Pathologic Processes; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Protein Kinase; Publishing; Regulation; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Structure; Syndrome; Systemic hypertension; Testing; Therapeutic; Tissues; Transgenic Organisms; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Ventricular; Ventricular Remodeling; base; blood pressure reduction; blood pressure regulation; constriction; dietary salt; improved outcome; in vivo; innovation; interest; mixed lineage kinase 3; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; preclinical study; pressure; prevent; protective effect; public health relevance; research study; response; sildenafil; therapeutic target

 DESCRIPTION (provided by applicant): This application proposes to explore a novel signaling pathway regulating the process of pathologic cardiac remodeling. Cardiac remodeling represents the pathologic alterations in ventricular structure and function which contribute to heart failure and death. Our laboratory has explored downstream anti-remodeling signaling regulated by the signaling molecule protein kinase G Iα (PKGIα). Our prior published studies have revealed a direct role of PKGIα in inhibiting pathologic cardiac remodeling in vivo. PKGI activating therapies are under investigation in humans with heart failure, but have been limited primarily by excess hypotension arising from PKGI induced vasodilation. In preliminary studies we have therefore explored downstream PKGIα substrates in the myocardium in order to identify signaling mechanism which may specifically inhibit remodeling but avoid excess vasodilation. Our preliminary data reveal mixed linage kinase 3 (MLK3) as a PKGIα anti-remodeling substrate. They also identify increased LV pressure overload-induced cardiac remodeling in MLK3 knockout mice, as well as systemic hypertension in these mice. Based on these and other preliminary data we propose to test the hypothesis that MLK3 mediates PKGIα anti-remodeling effects through kinase-dependent effects in the CM, and kinase-independent effects on vascular tone. We propose to test this hypothesis through 3 specific aims: SA1) To determine the role of MLK3 in mediating the anti-remodeling effects of PKGIα signaling; SA2) To determine the kinase-dependent mechanisms through which MLK3 inhibits cardiac remodeling; SA3) To determine the kinase-independent mechanisms through which MLK3 reduces blood pressure. These proposed studies utilize in vitro approaches as well as multiple innovative mouse models. Successful completion of these studies has the potential to identify MLK3 kinase activation as a novel therapeutic strategy for cardiac remodeling. Further, these studies will provide experimental evidence to address the novel paradigm that PKGIα inhibits cardiac remodeling and reduces blood pressure through independent signaling mechanisms.

 描述(申请人提供)：本申请建议探索一种新的信号通路，调节病理性心脏重塑的过程。心脏重塑是指导致心力衰竭和死亡的心脏结构和功能的病理改变。本实验室已经探索了受信号分子蛋白激酶G Iα(PKGIα)调控的下游抗重构信号。我们先前发表的研究已经揭示了PKGIα在体内抑制病理性心脏重塑中的直接作用。PKGI激活疗法正在研究中，用于患有心力衰竭的人类，但主要受到PKGI诱导的血管扩张引起的过度低血压的限制。因此，在初步研究中，我们探索了心肌中PKGIα的下游底物，以确定可能特异性地抑制重塑但避免过度血管扩张的信号机制。我们的初步数据显示，混合连接蛋白激酶3(MLK3)是一种PKGIα抗重构底物。他们还发现了MLK3基因敲除小鼠左室压力超负荷导致的心脏重构增加，以及这些小鼠的全身性高血压。基于这些和其他初步数据，我们建议检验这一假设，即MLK3通过对CM中的激酶依赖性作用和对血管张力的非依赖性作用来介导PKGIα的抗重构作用。我们建议通过三个特定的目标来验证这一假说：1)确定MLK3在介导PKGIα信号转导的抗重构效应中的作用；SA2)确定MLK3抑制心脏重构的依赖于激酶的机制；SA3)确定MLK3降低血压的非依赖于激酶的机制。这些拟议的研究利用了体外方法和多种创新的小鼠模型。这些研究的成功完成有可能将MLK3激酶激活确定为心脏重构的一种新的治疗策略。此外，这些研究将为PKGIα通过独立的信号机制抑制心脏重构和降低血压这一新范式提供实验证据。