The longterm goal of this project is to define the role of the phosphoinositide-3 kinase (PI3K) pathway in cardiac hypertrophy using transgenic and gene-targeted mice, with a focus on its role on cell size determination during nomal growth and in pathological conditions. Little is known regarding the critical mechanism that controls the myocyte size in vivo. While the growth hormone insulin-like growth factor-1 (IGF1) pathway is well-known to play a critical role in determining overall animal size in mammals, the link between IGF1 and the PI3K pathway in determining individual cell and organ size has not been established. Accordingly, we have recently created transgenic mice with perturbed PI3K activity in the heart. Interestingly, the mice expressing constitutively active PI3K develop moderate cardiac hypertrophy without myocardial dysfunction. The morphometric analysis indicated that cardiac hypertrophy is primarily due to an increase in cell size of the individual myocytes. In contrast, cardiac expression of a dominant-negative PI3K yielded a smaller heart with a concomitant decrease in cell size of individual myocytes. We have also created transgenic mice overexpressing the IGF1 receptor in the cardiac myocyte. Similar to the mice expressing constitutively active PI3K, the IGF1 receptor mice also develop moderate cardiac hypertrophy without signs of cardiac dysfunction. These results raise the possibility that the IGF1-PI3K pathway may play a critical role in determining heart size by regulating the size of cardiomyocytes during normal growth. Two known downstream targets of PI3K are the Akt (protein kinase B) and the p70/p85 ribosomal S6 kinase (S6K). However, their role in the cardiac growth in vivo has not been established. Therefore, we will determine the relative role of Akt and S6K for the cardiac hypertrophic effect of PI3K activation. In addition, in order to examine the role of PI3K, Akt, and S6K in pressure overload- induced hypertrophy, we will create aortic banding in the transgenic mice that express constitutively active or dominant- negative forms of these kinases. Furthermore, we will cross the PI3K transgenic mice with thyroid receptor transgenics and PKC transgenics generated by the Wondisford lab and the King lab, respectively. Accordingly, our Specific Aims are:
Specific Aim 1 : To confirm the role of PI3K in determining the size of the heart in the adult animal by a conditional transgenic system.
Specific Aim 2 : To examine whether PI3K is genetically downstream of IGF1/IGF1 receptor in the in vivo heart.
Specific Aim 3 : To determine genetic interactions among the PI3K pathway, PKC pathway, and thyroid hormone receptor signaling in cardiac hypertrophy.
Specific Aim 4 : To determine whether S6K is downstream of PI3K in determining the myocyte cell size in vitro and in vivo.
Specific Aim 5 : To determine the function of Akt in determining myocyte cell size and survival in vivo and in vitro.
Specific Aim 6 : To determine the role of PI3K, Akt, and S6K in modulating pressure overload hypertrophy. These studies will lead to a better understanding of the role of the PI3K pathway in determining the heart and myocyte size in physiological and pathological conditions in vivo.
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