Myofilament signaling and cardiac disorders

肌丝信号传导和心脏疾病

• 批准号: 9261596
• 负责人: R John Solaro
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-14 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261596
• 关键词: 1 year old; Ablation; Address; Admission activity; Affect; Agonist; Angiotensin II; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Chronic; Coupled; Data; Data Reporting; Development; Exercise; Familial Hypertrophic Cardiomyopathy; Fibrosis; Functional disorder; Genetic; Glycols; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hospitals; Hypertrophic Cardiomyopathy; Hypertrophy; Individual; Knockout Mice; Link; Measurement; Mechanics; Microfilaments; Modeling; Modification; Molecular; Mus; Mutation; Myocardium; Oxidative Stress; Pathologic; Pathway interactions; Peptides; Phosphorylation; Phosphotransferases; Physiological; Play; Production; Propane; Proteome; Publishing; Regulation; Reporting; Role; Running; SERCA2a; Sarcomeres; Signal Transduction; Sphingolipids; Stress; Testing; Therapeutic; Thin Filament; Transforming Growth Factor beta; Translating; Translations; United States; antitumor agent; constriction; experimental study; functional improvement; gain of function; inhibitor/antagonist; insight; mouse model; novel; novel therapeutics; p21 activated kinase; periostin; phospholamban; physiologic model; prevent; public health relevance; response; sphingosine 1-phosphate; stressor; therapeutic development

 DESCRIPTION (provided by applicant): Results of our published and preliminary studies provide strong evidence that p21-activated kinase (Pak1) is a pleiotropic kinase controlling contractility via signaling that alters cellular Ca2+-fluxes and myofilament Ca2+- response. Pak1 also acts as a hub in pathways suppressing common modes of acquired and familial hypertrophy, remodeling, and fibrosis. Our hypothesis is: activation of Pak1 represents a novel cardio- protective therapy acting to suppress effects of maladaptive cardiac stressors leading to cardiac remodeling, fibrosis and dysfunction. Understanding the mechanisms of Pak1 activation and its downstream mechanisms affecting signaling, Ca2+ fluxes and myofilament Ca2+ response is critical to overall understanding of cardiac signaling and to devising strategies for selective activation of Pak1 in the myocardium. Our overall objective is to determine Pak1 related mechanisms involving signaling cascades, Ca2+-fluxes, and myofilament Ca2+- response in the context of a physiological response (exercise), in acquired heart failure (Ang II stress), and in a genetic hypertrophic cardiomyopathy (HCM). Preliminary data strongly support the likelihood that our aims will significantly advance understanding of the control of cardiac function. In Aim #1 our objective is to determine mechanisms by which activators of Pak1 ameliorate maladaptive responses to chronic cardiac stressor - AngII and play a role in physiological hypertrophy with exercise. In Aim #2, we test the hypothesis that that activators of Pak1 are able to prevent and/or inhibit maladaptive responses associated with familial hypertrophic cardiomyopathy linked to thin filament mutations by activating Serca2a, reducing oxidative stress and blocking of NFAT and periostin/TGFβ pathways. Our objective in Aim #3 is to determine effects of Pak1 signaling on molecular mechanisms at the level of sarcomeres in hearts stressed by physiological, maladaptive (Ang II) and familial (HCM) hypertrophy. Results of our proposed experiments provide insights into previously unappreciated mechanisms of cardiac remodeling and approach to cardio-protection. Our studies translate experimental findings into realistic and novel therapies for hypertrophic remodeling and fit the general theme of our approaches to fully integrate sarcomeric signaling into overall adaptive and maladaptive responses in the myocardium.

 描述（由申请人提供）：我们已发表和初步研究的结果提供了强有力的证据，证明p21激活激酶（Pak 1）是一种多效性激酶，通过改变细胞Ca 2+通量和肌丝Ca 2+反应的信号传导来控制收缩性。Pak 1还在抑制获得性和家族性肥大、重塑和纤维化的常见模式的途径中充当枢纽。我们的假设是：Pak 1的激活代表了一种新的心脏保护疗法，其作用是抑制导致心脏重塑、纤维化和功能障碍的适应不良的心脏应激源的作用。了解Pak 1激活的机制及其影响信号传导、Ca 2+通量和肌丝Ca 2+反应的下游机制对于全面了解心脏信号传导和设计心肌中Pak 1选择性激活的策略至关重要。我们的总体目标是确定Pak 1相关机制，涉及信号级联，Ca 2+通量，肌丝Ca 2+反应的背景下的生理反应（运动），在获得性心力衰竭（血管紧张素II应激），并在遗传性肥厚型心肌病（HCM）。初步数据强烈支持我们的目标将显着推进心脏功能控制的理解。在目标#1中，我们的目标是确定Pak 1激活剂改善对慢性心脏应激源- AngII的适应不良反应的机制，并在运动的生理性肥大中发挥作用。在目标#2中，我们检验了Pak 1的激活剂能够通过激活Serca 2a、减少氧化应激和阻断NFAT和骨膜蛋白/TGFβ途径来预防和/或抑制与细纤维突变相关的家族性肥厚型心肌病相关的适应不良反应的假设。我们的目标#3是确定Pak 1信号传导对生理性、适应不良性（Ang II）和家族性（HCM）肥大应激心脏中肌节水平的分子机制的影响。我们提出的实验结果提供了以前不受重视的心脏重塑机制和心脏保护方法的见解。我们的研究将实验结果转化为肥厚性重塑的现实和新疗法，并符合我们方法的总体主题，即将肌节信号传导完全整合到心肌的整体适应性和适应不良反应中。