Loren J. Field, Ph.D.
Professor of Medicine: Indiana University School of Medicine
Clinical Section: Pediatric Cardiology
Basic Science Joint Appointment: Cellular and Integrative Physiology
Staff Investigator: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
Postdoctoral Fellowship: Roswell Park Memorial Institute, Buffalo, New York
Ph.D.: State University of New York at Buffalo, 1982
Current Research Interests:
Use of transgenic models, molecular biology and cell culture approaches to understand the molecular regulation of the cardiomyocyte cell cycle and terminal differentiation.
Research:
During embryonic and early neonatal development the myocardium undergoes a period of hyperplastic growth which results in an exponential increase in the number of myocytes that constitute the heart. Soon after birth cardiomyocyte proliferation ceases and subsequent increases in myocardial mass is accomplished by cellular hypertrophy. The molecular basis for the transition from hyperplastic to hypertrophic myocardial growth remains largely unknown. Anomalies in the regulation of cardiomyocyte proliferation can give rise to congenital heart defects (ie hypoplastic ventricle syndromes). Moreover, because cardiomyocyte cell cycle withdrawal is irreversible, cell death with an ensuing loss of myocardial function is observed in many forms of adult cardiovascular disease. The ability to therapeutically program cardiomyocyte proliferation might provide a means to treat some forms of pediatric and adult cardiovascular disease. Work in our laboratory is focused on developing strategies with which to augment cardiomyocyte proliferation in both developing and adult hearts. Several current approaches are:
1. Characterize genes which impact upon cardiomyocyte proliferation and terminal differentiation during development. There are many descriptive studies examining the expression of known cell cycle regulatory genes during cardiomyocyte terminal differentiation. However, gene transfer experiments are need to establish if a given candidate gene plays a causative role in the process. Accordingly, we have used transgenic mice to test the role of a number of cell cycle regulatory genes, and have identified several candidates which might be useful for engendering therapeutic myocardial growth. We have also performed structure:function analyses on the Tuberous Sclerosis (TS) genes: TS is a childhood caFebruary 6, 2008nign myocardial tumors. We have generate several dominate interfering TS mutants which alter cardiomyocyte terminal differentiation in transgenic animals.
2. Identification of genes which program cardiomyocyte proliferation in a genetic model of cardiac tumorigenesis. We have generated transgenic mice which express the SV40 Large T Antigen oncoprotein in the heart. These mice develop myocardial tumors comprised of differentiated, proliferating cardiomyocytes. We have used cell lines derived from the transgenic mouse tumors to identify the myocardial proteins which bind to T-Antigen: binding proteins identified by analogous approaches with other cell types have proven to be important cell cycle regulators. Current efforts are centered on cloning these T-Antigen binding proteins, and establishing their function using both in vitro (cell transfection and molecular analyses) and in vivo (transgenic and knock-out mice) approaches.
3. Determining if intracardiac engraftment of donor myocytes can be used to augment cardiac function. We have recently shown that fetal cardiomyocytes can be used to form stable grafts in adult hearts using murine and canine models. Clinical application of this approach is dependent upon the identification of a suitable source of donor cells. Potential candidates include genetically modified skeletal myoblasts and cardiomyocytes derived from ES cells. Current efforts are focused on determining the spectrum of cardiomyocytes which can differentiate from ES cells in vitro (ie atrial, ventricle, purkinje and pacemaker cells), as well as establishing the molecular determinants of donor cell survival and proliferation following engraftment.
