The overarching goal of this research proposal is to understand how the heart responds to alterations in actin, the principal component of thin filaments involved in generating contractile force by the heart. Our previous work strongly supports the hypothesis that the conserved structural differences between cardiac actin and enteric actin are related to unique functional differences between these two proteins. Here, we hypothesize that differences between cardiac actin and enteric actin at position 1 (D->-) and/or position 360 (Q->P) will account for the functional alterations. Thus, the effect of these amino acid alterations in cardiac actin will be assessed in terms of structural, molecular, and physiological changes in the myocardium. We also have transgenically introduced two mutant cardiac actins (R312H and E361G) into the mouse heart that are associated with idiopathic dilated cardiomyopathies in humans and another (A295S) which is associated with hypertrophic cardiomyopathy. This approach will permit us to define the progression of the aberrant phenotype, if any, and provide insights into the pathogenesis associated with these mutations. We will also determine whether increased expression of skeletal or vascular actin is required for survival of cardiac actin-deficient mice. The hypothesized requirement for skeletal and vascular actin for survival of cardiac actin null animals to birth and beyond will be tested using mice that are cardiac actin null and skeletal actin null or vascular actin null. The impact of a deficiency in skeletal actin or vascular actin on the survival of cardiac actin heterozygotes will also be of interest. Finally, we plan to seek out modifier loci that affect the survival of cardiac actin heterozygotes. We have recently obtained evidence suggesting that there is a marked strain-specific variation in survival of mice that are heterozygous for the null cardiac actin allele. A reciprocal back-cross strategy will be applied and genes that modify the survival phenotype will be sought using a genome-wide scan for linkage. These approaches will provide new insights into the pathogenesis of heart failure in this model and, in future studies, hopefully permit the identification of candidate genes that affect survival in human populations. ? ?
| Abdelwahid, Eltyeb; Pelliniemi, Lauri J; Szucsik, John C et al. (2004) Cellular disorganization and extensive apoptosis in the developing heart of mice that lack cardiac muscle alpha-actin: apparent cause of perinatal death. Pediatr Res 55:197-204 |
| Kumar, A; Crawford, K; Flick, R et al. (2004) Transgenic overexpression of cardiac actin in the mouse heart suggests coregulation of cardiac, skeletal and vascular actin expression. Transgenic Res 13:531-40 |
| Hofmann, Wilma A; Stojiljkovic, Ljuba; Fuchsova, Beata et al. (2004) Actin is part of pre-initiation complexes and is necessary for transcription by RNA polymerase II. Nat Cell Biol 6:1094-101 |
| Martin, Anne F; Phillips, Ronald M; Kumar, Ajit et al. (2002) Ca(2+) activation and tension cost in myofilaments from mouse hearts ectopically expressing enteric gamma-actin. Am J Physiol Heart Circ Physiol 283:H642-9 |
