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（由适用提供）：我们已发表和初步研究的结果提供了有力的证据，表明P21激活激酶（PAK1）是通过信号来改变细胞Ca2+ - 荧光液和肌膜CA2+响应的信号，是一种多效激酶控制收缩力。 PAK1还充当途径中的枢纽，从而抑制了获得的获得的共同模式和家庭肥大，重塑和纤维化。我们的假设是：PAK1的激活代表了一种新型的心脏保护疗法，该治疗可抑制导致心脏重塑，纤维化和功能障碍的不良心脏心脏应激源的作用。了解PAK1激活的机制及其影响信号传导的下游机制，CA2+通量和肌丝Ca2+响应对于整体理解心脏信号传导和设计策略以选择性激活PAK1在心肌中至关重要。我们的总体目标是确定涉及的PAK1相关机制。在物理反应（运动），获得的心力衰竭（ANG II应激）以及遗传性肥厚性心肌病（HCM）中，信号传导级联反应，Ca2+ - 弹药和肌丝Ca2+反应。初步数据在很大程度上支持我们的目标会大大推动对心脏功能控制的理解的可能性。在AIM＃1中，我们的目标是确定PAK1的激活因素对慢性心脏压力源的适应不良反应 - ANGII并通过运动在物理肥大中发挥作用。在AIM＃2中，我们检验了以下假设：PAK1的激活剂能够预防和/或抑制与家庭肥大心肌病有关的疾病，与薄丝突变相关的家庭肥大性心肌病，通过激活SERCA2A，减少NFAT的氧化应激和NFAT和周期/TGFβ途径的氧化应激和阻塞。我们的目标＃3的目标是确定PAK1信号传导对由身体，适应不良（ANG II）和家族（HCM）肥大压力的心脏中肉瘤水平上的分子机制的影响。我们提出的实验的结果为心脏重塑的先前未批准的机制和心脏保护方法提供了见解。我们的研究将实验发现转化为肥厚型重塑的现实和新颖疗法，并符合我们的方法的一般主题，以使肉瘤信号完全整合到心肌中的总体适应性和不良适应性反应中。