The overall goal of the proposed research is to investigate how calmodulin overexpression causes cardiac myocyte hypertrophy and hyperplasia and perhaps heart failure. Calmodulin (CaM) is a ubiquitous intracellular Ca2+ receptor known to regulate cell proliferation in a number of cell types; we have shown that increased CaM levels targeted to cardiac myocytes by the atrial natriuretic hormone (ANF) promoter in transgenic mice lead to cardiac enlargement characterized by exaggerated myocyte hypertrophy and hyperplasia. Furthermore, there is excess mortality in neonates from the line of transgenic mice expressing the highest levels of CaM.
The first aim i s to evaluate transgenic mice that die prematurely compared with transgenic mice with normal lifespans. The approach is to examine CaM levels, expression of genes related to growth (i.e. proto-oncogenes) or are markers of hypertrophy, and relative levels of activated multifunctional Ca2+ /CaM protein kinase II (CaMK II), a potential mediator or the CaM effect.
Aim 2 is to determine the effect of dither reinduced or persistent expression of CaM in the ventricles of transgenic mice. Two approaches will be used: (1) to reinduce the CaM transgene in adult animals of the existing lines using pharmacologic agents known to induce the ANF promoter, again examining changes, over time, in heart size, mortality, and expression of the genes listed above; and (2) to develop a new line of transgenic mice with CaM expression targeted to the heart by the iso=-ANF promoter; use of this promoter should result in continued expression of CaM in the ventricles into adulthood. The animals will be examined as described above. These studies may further define the relationship of CaM levels in cardiac myocytes to the degree of growth response and development of heart failure and possibly identify change in expression of genes, that accompany the progression from cardiac hypertrophy to heart failure in this model.
The final aim i s to test the hypothesis that CaMK II is central to the cardiomyocyte growth response induced by CaM. The approach is to develop transgenic mice bearing a constitutively active CaMK II gene under control of a cardiomyocyte specific promoter and characterize the cardiac growth response of these animals.
Showing the most recent 10 out of 21 publications
