The primary goal of this Mentored Minority Faculty Development Award is to prepare the applicant for a career as an independent investigator in cardiac research. The laboratories of Drs. Roger Hajjar and Anthony Rosenzweig, in the Cardiovascular Research Center, will provide the applicant with a rich intellectual environment from which to gain a rigorous foundation in molecular biology and somatic gene transfer. A current strategy of cancer therapy involving pharmacologic inactivation of the erbB-2(Her2) receptor in combination with doxorubicin has resulted in significant tumor response rates but has been complicated by a high rate of cardiotoxicity. The erbB-2 receptor and erbB ligand, neuregulin, have been demonstrated to be important to cardiac organogenesis as well as normal cardiomyocyte physiology. Our laboratory has demonstrated that partial inactivation of the receptor with an inhibitory monoclonal antibody induces apoptosis and decreases Akt phosphorylation in cultured neonatal, rat cardiomyocytes. This proposal is based on several hypotheses: 1) ErbB-2 receptor activates PI-3-kinase in cardiac myocytes. 2) ErbB-2 activation promotes cardiomyocyte survival through Akt and MAPK. 3) The synergistic myopathic effect observed with doxorubicin and erbB-2 blockade is mediated through the further inhibition of PI-3K signal cascades. 4) Apoptosis contributes significantly to the pathogenesis of cardiac dysfunction in erbB-2 antagonist and doxorubicin induced heart failure. To test these hypotheses we will study cardiomyocytes in vitro and in vivo, exposed to an inhibitory monoclonal antibody to the erbB-2 receptor, the protein ligand, neuregulin, and doxorubicin.
In Specific Aim 1 we will examine the effects of erbB-2 activation alone and in combination with doxorubicin on cardiomyocyte function, and apoptosis in vitro.
In Specific Aim 2 we will investigate the effect of erbB-2 receptor activation and antagonism on PI3k/Akt and MAPK signaling.
In Specific Aim 3 we will study the effects of erbB-2 inhibition in a rodent model of doxorubicin induced heart failure. Understanding the role of this receptor, and its relationship to signaling pathways modulating cardiomyocyte apoptosis and viability may provide a basis for novel therapeutic approaches.
| Grazette, Luanda P; Rosenzweig, Anthony (2005) Role of apoptosis in heart failure. Heart Fail Clin 1:251-61 |
| Grazette, Luanda P; Boecker, Wolfgang; Matsui, Takashi et al. (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231-8 |
