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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

基本信息

批准号：
9260042
负责人：
Robert Morris Blanton
金额：
$ 42.38万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9260042
关键词：
Address Adult Adverse effects Arteries Binding Blood Blood Pressure Blood Tests Blood Vessels Brain natriuretic peptide Cardiac Cardiac Myocytes Cardiovascular system Cause of Death Cessation of life Clinical Clinical Trials Cyclic AMP-Dependent Protein Kinases 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 Muscle Cells Mutation Myocardium Myography Pathologic Pathologic Processes Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Protein Kinase Publishing Regulation Reporter Resistance Role Signal Pathway Signal Transduction Signaling Molecule 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 cGMP-dependent protein kinase Ibeta constriction dietary salt experimental study 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 response sildenafil therapeutic candidate therapeutic target vascular contributions

项目摘要

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（由申请人提供）：本申请提出探索调节病理性心脏重塑过程的新信号通路。心脏重构是指心室结构和功能的病理性改变，导致心力衰竭和死亡。本实验室探索了信号分子蛋白激酶G Iα（PKGIα）调控的下游抗重塑信号通路。我们先前发表的研究揭示了PKGIα在体内抑制病理性心脏重塑中的直接作用。PKGI激活疗法正在心力衰竭患者中进行研究，但主要受到PKGI诱导的血管舒张引起的过度低血压的限制。因此，在初步研究中，我们探索了心肌中的下游PKGIα底物，以确定可能特异性抑制重塑但避免过度血管舒张的信号传导机制。我们的初步数据显示混合谱系激酶3（MLK 3）作为PKGIα抗重塑底物。他们还确定了MLK 3基因敲除小鼠中LV压力超负荷诱导的心脏重塑增加，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MLK 3通过CM中的激酶依赖性作用和对血管张力的激酶非依赖性作用介导PKGIα抗重塑作用的假设。我们建议通过3个具体目标来验证这一假设：SA 1）确定MLK 3在介导PKGIα信号传导的抗重塑作用中的作用; SA 2）确定MLK 3抑制心脏重塑的激酶依赖性机制; SA 3）确定MLK 3降低血压的激酶非依赖性机制。这些拟议的研究利用体外方法以及多种创新的小鼠模型。这些研究的成功完成有可能将MLK 3激酶激活确定为心脏重塑的新治疗策略。此外，这些研究将提供实验证据，以解决PKGIα通过独立的信号传导机制抑制心脏重塑和降低血压的新范式。