Our laboratory has a long-standing interest in the development, progression and regression (treatment) of heart failure, particularly as it relates to b(beta)-adrenergic receptor (b-AR) signaling. We have recently identified a number of novel genes that are associated with both the development and regression of cardiac disease using a large-scale gene expression profiling approach with both mouse and human heart tissue from non-failing, failing, and phenotypically"rescued" cardiac phenotypes. We are now using a translational approach to investigate the functional cardiac and b-AR-related relevance of these genes, employing techniques that range from basic in vitro biochemistry, pharmacology and cell biology to in vivo cardiac phenyotyping. In general, there are three main projects moving forward in the lab:

1) The first project stems from our mouse gene expression study, where we were able to blindly predict cardiac phenotype (Normal, Heart Failure, and "Rescue") from cardiac gene expression: our most significant predictors were cytoarchitectural genes. We are investigating the role of 3 of these genes in cardiac function, including their interaction with and regulation by b-ARs, using various techniques: transfected cell culture, infected primary cardiac myocyte cell culture, general knockout mice, and cardiac-specific overexpression mice.

2) The second project stems from our findings that, at the level of gene and protein expression, there are distinct differences between ischemic and dilated cardiomyopathy in humans, and that there are distinct changes in gene expression that occur in the heart following mechanical circulatory support (left ventricular assist device). We will continue to investigate/validate differential gene expression between the two etiologies of heart failure, as well as before and after mechanical circulatory support. Importantly, we are investigating the role of inflammatory cytokines and their potential interaction with both adrenergic and angiotensin receptors in ischemia/reperfusion injury compared to dilated cardiomyopathy using transgenic and knockout animal models.

3) The third project is a bioinformatic approach, utilizing existing gene expression data from both ourselves and others, as well as data to be obtained in future microarray studies, to attempt to more clearly define the gene expression profiles that distinguish particular phenotypes or etiologies of heart faliure, including both the development and "rescue" of heart failure in animals an humans. We will also begin to identify genes common between cardiac and vascular disease.

Blaxall BC, Pende A, Wu SC and Port JD. Correlation between intrinsic mRNA stability and affinity of AUF1 (hnRNP D) and HuR for A+U-rich mRNAs. Mol. Cell. Biochem. 232:1-11, 2002.

Blaxall BC, Tschannen-Moran BM, Milano CA and Koch WJ. Differential gene expression and genomic patient stratification following Left Ventricular Assist Device (LVAD) support in humans. J. Amer. Coll. Card. 41:1096-1106, 2003. (see also Editorial Comment, Bristow MR, J Amer. Coll. Card., 41:1107-1108).

Blaxall BC, Spang R, Rockman HA, Lefkowitz RJ and Koch WJ. Differential myocardial gene expression in the development and rescue of murine heart failure. Physiol. Genom. 15:105-114, 2003.

Blaxall BC and Koch WJ. Transgenic mouse models of cardiovascular function and disease. Handbook of Experimental Pharmacology: Transgenic Models in Pharmacology, Lutz Hein and Stefan Offermanns (editors). Springer-Verlag,, 346-367, 2003.

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