This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of our research program is to define the role of Myc in regulating angiogenesis during tumorigenesis and development. Our laboratory has previously demonstrated that c-Myc can act as a master regulator of both pro- and anti-angiogenic factors during embryonic development and tumor formation. Loss of c-Myc results in hematopoietic and vascular defects. Moreover, both c-Myc- and N-Myc-deficient mice display cardiovascular defects, yet to date these defects have not been well characterized. We will attempt to analyze these defects through several different experimental approaches. First, we will use conditional knockout mice to examine the effect of Myc loss in the heart (specifically in cardiomyocytes) during embryonic development and following birth. Either whole hearts (in vivo and in vitro) or cells (in vitro) can then be stressed and cellular responses can be measured both physically and biochemically. Secondly, we will generate a transgenic mouse that expresses c-Myc specifically in fibroblasts (using the DDR2 promoter) and examine the effect of Myc activation on heart development, again in the developing embryo and in the adult animal. Finally, we will examine the exact mechanism(s) of how Myc regulates angiogenic factors (both positively and negatively) and what role this plays in development of the cardiovascular system.
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