After being introduced to the molecular cardiology laboratories at the University of Chicago, I was fortunate to be given the opportunity to pursue both my clinical and my research training at an institution which values the role of the physician scientist. As I progressed through internal medicine residency and cardiology fellowship, I saw the dramatic impact that physician scientists had, not only in the care of the patient, but in the understanding of the diseases they studied. I consider myself truly fortunate to have identified several key mentors who have invested so much time and effort in my development. As my clinical training comes to a close and I begin the learning that comes with being a junior faculty member, I am acutely aware of the importance of experienced mentorship as I transition to become an independent investigator. The University of Chicago not only provides the resources and clinicians to develop me as a physician-scientist, it provides the precious resources, support, and mentors at this critical time in my career. With so many aspects of acquired heart diseases recapitulating many of the molecular pathways regulating cardiogenesis, I was drawn into the cardiac development laboratory of Dr. Eric Svensson. There I began studying key transcription factors controlling coronary vessel and cardiomyocyte development. My research interests then turned to the relatively new field microRNAs, an emerging class of regulatory molecules with key roles in development and disease. Despite the broad range of biologic processes which they regulate, only a few microRNAs have been studied thoroughly. We have found that one particular microRNA, microRNA-130a, is highly expressed in the developing mouse heart and targets a key transcriptional regulator of cardiac development, FOG-2, and likely many more. Given the complex signaling requirements and protein dosage sensitivity in cardiac development, I hypothesize that the levels of microRNA-130a may also be important for normal heart development through its action on other key targets. To study this, I have proposed to pursue to following aims: 1) Validate the predicted targets of miR-130a relevant to cardiac development using a transgenic mouse model over expressing microRNA-130a. 2) Determine the mechanism of ventricular wall hypoplasia and embryonic lethality in the 2MHC-miR-130a mice through serial histological staining and assessment of cardiomyocyte apoptosis and proliferation. 3) Elucidate the regulatory elements controlling microRNA-130a expression by defining the temporal-spatial pattern of microRNA-130a expression as well as performing both in vitro and in vivo functional promoter assays. With the emerging understanding of microRNAs in the regulation of gene expression, their role in heart development and congenital heart disease merits further investigation. MicroRNA-130a, through its interaction with key transcriptional regulators of cardiac development, may play a significant role in normal heart development, as well as being important in acquired heart disease in the adult.
Project Narrative The field of microRNAs is rapidly growing and changing our fundamental understanding of cardiovascular biology, but despite the broad range of functions, which these small molecules regulate, only a handful have been studied. MicroRNA-130a, through its potential targeting of several regulators of cardiac development, may play a key role in normal cardiac formation and the development of congenital heart diseases.
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