The overall theme of the above PPG application will continue to be the identification of novel signaling molecules and pathways that contribute to the pathogenesis of heart failure (HF) after cardiac injury and also to study potential intersecting signaling and cellular mechanisms for repair of compromised myocardium. The proposal specifically will aim to identify critical molecular targets involved in abnormal myocardial responses to stress and subsequent repair or reversal of cardiac injury. Importantly, our studies will be done with a vision towards identifying new therapeutic strategies for reversing HF, which is something desperately needed as the incidence of this devastating disease continues to rise. Although improvements have been made in the management of HF, deaths are still increasing and it is imperative to find more effective therapies. Our efforts will come from multiple but complimentary directions and all investigators will use newly developed mouse models to test individual project hypotheses focused on the PPG theme. This PPG is being led by project leaders who are distinguished scientists in the HF arena with a long history of productivity, and who are all faculty at Temple University School of Medicine. The fact that all members are in the same building should only enhance our close collaborations that have led to success over the first funding cycle of and which has produced the described integrative projects in the current application. The themes of each project are: Project 1 (Koch) will study how the novel activity of G protein-coupled receptor kinase-5 (GRK5), including in the nucleus, alters myocardial responses to hypertrophic and ischemic stress that injure the heart to promote remodeling and eventual HF;Project 2 (Feldman) will investigate novel roles of arginine vasopressin (AVP) type 1A receptors in cardiac injury induction and protection, including differential mechanistic involvement of G protein- versus GRK-biased signaling in these processes;Project 3 (Houser) will study how calcium (Ca2+) entry through specific transient receptor potential (TRP) channels alter hypertrophic and remodeling processes of the heart following cardiac injury and how their modification by G protein signaling molecules and protein kinases may influence downstream signaling events. These three projects will continue to be supported by four Core units: Administrative (Koch);Mouse Physiology/Surgery (Gao);Molecular and Cellular Imaging (Tilley);and Gene Vector (Rabinowitz). Importantly, all Project leaders have expertise in translating their basic science results/discoveries, which represents a strength of our program.
Heart Failure remains a major health problem and there continues to be a need to develop innovative treatments to minimize cardiac injury and repair the failing heart. Understanding molecular mechanisms involved in cardiac injury and repair is imperative in order to begin to develop these novel therapies. All projects within this Program Project have goals to move towards translating discoveries and developing novel therapies.
|Ahmad, Firdos; Lal, Hind; Zhou, Jibin et al. (2014) Cardiomyocyte-specific deletion of Gsk3? mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696-706|
|Bathgate-Siryk, Ashley; Dabul, Samalia; Pandya, Krunal et al. (2014) Negative impact of *-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension 63:404-12|
|Scimia, Maria Cecilia; Blass, Benjamin E; Koch, Walter J (2014) Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy. Expert Rev Cardiovasc Ther 12:733-41|
|Lal, Hind; Ahmad, Firdos; Parikh, Shan et al. (2014) Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease. Circ J 78:1514-9|
|Hullmann, Jonathan E; Grisanti, Laurel A; Makarewich, Catherine A et al. (2014) GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity. Circ Res 115:976-85|
|Miller, Barbara A; Hoffman, Nicholas E; Merali, Salim et al. (2014) TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria. J Biol Chem 289:7615-29|
|Tilley, Douglas G; Zhu, Weizhong; Myers, Valerie D et al. (2014) ?-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling. Circulation 130:1800-11|
|Feldman, Arthur M; Begay, Rene L; Knezevic, Tijana et al. (2014) Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy. J Cell Physiol 229:1697-702|
|Scimia, Maria C; Gumpert, Anna M; Koch, Walter J (2014) Cardiovascular gene therapy for myocardial infarction. Expert Opin Biol Ther 14:183-95|
|Wang, JuFang; Song, Jianliang; Gao, Erhe et al. (2014) Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 306:H1066-77|
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