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：
9899289
负责人：
Robert Morris Blanton
金额：
$ 42.75万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899289
关键词：
Address Adult 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 Endothelium 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 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 side effect 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）：本申请旨在探索调节病理性心脏重塑过程的新信号通路。心脏重塑代表导致心力衰竭和死亡的心室结构和功能的病理改变。我们之前发表的研究揭示了 PKGIα 在抑制体内病理性心脏重塑中的直接作用。治疗方法正在对患有心力衰竭的人类进行研究，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构但避免的信号传导机制。我们的初步数据显示混合系激酶 3 (MLK3) 作为 PKGIα 抗重构底物，他们还发现 MLK3 中左心室压力超负荷增加会导致心脏重构。基于这些和其他初步数据，我们建议测试 MLK3 通过 CM 中的激酶依赖性作用和对血管张力的激酶依赖性作用介导 PKGIα 抗重塑作用的假设。我们建议通过 3 个具体目标来检验这一假设： SA1) 确定 MLK3 在介导 PKGIα 信号传导的抗重塑作用中的作用； SA2) 确定 MLK3 发挥作用的激酶依赖性机制；抑制心脏重塑；SA3) 确定 MLK3 降低血压的独立激酶机制。这些拟议的研究利用体外方法以及多种创新的小鼠模型，有可能将 MLK3 激酶激活确定为一种降低血压的机制。此外，这些研究将为解决 PKGIα 通过独立信号机制抑制心脏重塑和降低血压的新范例提供实验证据。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling.

条件性敲除激活素样激酶 1 (ALK-1) 会导致心力衰竭，但不会导致适应不良重塑。

DOI：
发表时间：
2017-05
期刊：
影响因子：
1.5
作者：
Morine, Kevin J;Qiao, Xiaoying;Paruchuri, Vikram;Aronovitz, Mark J;Mackey, Emily E;Buiten, Lyanne;Levine, Jonathan;Ughreja, Keshan;Nepali, Prerna;Blanton, Robert M;Karas, Richard H;Oh, S Paul;Kapur, Navin K
通讯作者：
Kapur, Navin K

JNK and cardiometabolic dysfunction.

JNK 和心脏代谢功能障碍。