Myofilament signaling and cardiac disorders

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 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.