Regulation of cardiac stress responses by Rho kinase

Rho 激酶调节心脏应激反应

基本信息

批准号：
8665458
负责人：
Lei Wei
金额：
$ 38.22万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665458
关键词：
Actins Address Adverse effects Age-Months Angiotensin II Animal Model Apoptosis Apoptotic Biology Cardiac Cardiac Death Cardiac Myocytes Cardiotoxicity Cell Adhesion Cell Death Cell Survival Cells Cerebrovascular Spasm Cessation of life Characteristics Chronic Clinic Clinical Research Clinical Trials Cytoskeleton Data Dilated Cardiomyopathy Disease Doxorubicin Embryo Etiology Exhibits Family Fibroblasts Fibrosis Focal Adhesion Kinase 1 Functional disorder Genetic Processes Goals Grant Guanosine Triphosphate Phosphohydrolases Heart Diseases Heart Hypertrophy Heart failure Human In Vitro Infusion procedures Japan Knockout Mice Knowledge LIMK1 gene Left Left Ventricular Hypertrophy Mediating Modeling Mus Myosin ATPase Names Pathogenesis Pathologic Pathway interactions Phosphorylation Phosphotransferases Play Protein Isoforms ROCK1 gene Regulation Research Rho-associated kinase Role Signal Transduction Specificity Stimulus Stress Structure Subarachnoid Hemorrhage Sudden Death Takeda brand of pioglitazone hydrochloride Testing Therapeutic Intervention Ventricular bench to bedside biological adaptation to stress cofilin design effective therapy fasudil human disease human morbidity human mortality improved in vivo inhibitor/antagonist insight kinase inhibitor member novel polymerization pressure prevent public health relevance research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Heart failure remains a leading cause of human morbidity and mortality. Rho kinase (also named ROCK) has recently emerged as a potential therapeutic target for the treatment of cardiac diseases with the overall promising studies showing beneficial effects of ROCK inhibitors in experimental and clinical studies. However, one important question needing to be addressed is whether ROCK truly represents a viable target for the treatment of human disease as currently available ROCK inhibitors have broad specificity. In addition, the two members of the ROCK family, ROCK1 and ROCK2, are inhibited by ROCK inhibitors with equal potency, and little is known about ROCK isoform functions in vivo. We recent discovered that systemic ROCK1 deficiency is protective against cardiac decompensation and the anti-apoptotic effect of ROCK1 deficiency is a critical contributor. In contrast to the beneficial effects of ROCK1 deletion, we observed that cardiac-specific ROCK2 deficiency results in spontaneous cardiac hypertrophy and dysfunction, suggesting a novel role for ROCK2 in cardiac protection. Our in vitro studies using ROCK1 or ROCK2 deficient embryo-derived fibroblasts support a novel mechanistic concept that ROCK1 preferentially mediates stress-induced acto-myosin contraction via the ROCK1/MYPT/MLC pathway leading to increased cell death, while ROCK2 preferentially contributes to actin polymerization via the ROCK2/LIMK/cofilin pathway leading to improved cell survival under stress conditions. The goal of this application is to dissect isoform functions of ROCK in hypertrophic cardiac remodeling and to test a novel central hypothesis that ROCK1 and ROCK2 are functionally different in regulating cardiomyocyte death and cardiac remodeling in response to cardiac stress. Specific Aim 1 will test the hypothesis that ROCK2 promotes cardiomyocyte survival and cardiac protection. The studies will further characterize the onset and progression of spontaneous cardiac hypertrophy in cardiac-specific ROCK2 knockout mice, and will determine if conditional ROCK2 deletion in cardiomyocytes accelerates heart failure progression. Specific Aim 2 will determine the ultimate role of ROCK1 in cardiac decompensation. The studies will determine if conditional ROCK1 deletion in cardiomyocytes can limit the progression of heart failure when cardiac hypertrophy or dilated cardiomyopathy has already occurred through chronic pressure overload. Specific Aim 3 will test the hypothesis that ROCK1 and ROCK2 play opposite roles in mediating stress-induced cardiomyocyte death and characterize the underlying mechanisms. Results of these studies will significantly advance our knowledge in ROCK isoform pathophysiology and inform clinical trials testing ROCK pan- inhibitors, and eventually isoform selective inhibitors, with the ultimate goal of developing therapeutic interventions to prevent cardiomyocyte death and reduce heart failure progression.

描述（由申请人提供）：心力衰竭仍然是人类发病和死亡的主要原因。 Rho 激酶（也称为 ROCK）最近已成为治疗心脏病的潜在治疗靶点，总体有前景的研究表明 ROCK 抑制剂在实验和临床研究中具有有益作用。然而，需要解决的一个重要问题是，ROCK 是否真正代表了治疗人类疾病的可行靶点，因为目前可用的 ROCK 抑制剂具有广泛的特异性。此外，ROCK 家族的两个成员 ROCK1 和 ROCK2 受到 ROCK 抑制剂具有同等效力的抑制，而关于 ROCK 亚型在体内的功能知之甚少。我们最近发现，全身性 ROCK1 缺陷可预防心脏代偿失调，而 ROCK1 缺陷的抗凋亡作用是一个关键因素。与 ROCK1 缺失的有益效果相反，我们观察到心脏特异性 ROCK2 缺陷会导致自发性心脏肥大和功能障碍，这表明 ROCK2 在心脏保护中具有新的作用。我们使用 ROCK1 或 ROCK2 缺陷的胚胎来源成纤维细胞进行的体外研究支持了一种新的机制概念，即 ROCK1 优先通过 ROCK1/MYPT/MLC 途径介导应激诱导的肌动球蛋白收缩，导致细胞死亡增加，而 ROCK2 优先促进肌动蛋白聚合通过 ROCK2/LIMK/cofilin 途径提高细胞在应激条件下的存活率。本申请的目的是剖析 ROCK 在肥厚性心脏重塑中的亚型功能，并测试一个新的中心假设，即 ROCK1 和 ROCK2 在调节心肌细胞死亡和响应心脏应激的心脏重塑方面具有功能不同。具体目标 1 将检验 ROCK2 促进心肌细胞存活和心脏保护的假设。这些研究将进一步表征心脏特异性 ROCK2 敲除小鼠自发性心脏肥大的发生和进展，并将确定心肌细胞中条件性 ROCK2 缺失是否会加速心力衰竭进展。具体目标 2 将确定 ROCK1 在心脏代偿失调中的最终作用。这些研究将确定当慢性压力超负荷已经发生心脏肥大或扩张型心肌病时，心肌细胞中条件性 ROCK1 缺失是否可以限制心力衰竭的进展。具体目标 3 将检验 ROCK1 和 ROCK2 在介导应激诱导的心肌细胞死亡中发挥相反作用的假设，并描述潜在机制。这些研究的结果将显着增进我们对 ROCK 同工型病理生理学的了解，并为测试 ROCK 泛抑制剂以及最终同工型选择性抑制剂的临床试验提供信息，最终目标是开发治疗干预措施以预防心肌细胞死亡并减少心力衰竭进展。