Basic Research

Dr. Takeshi Tsuda has completed participation in the funded NIH COBRE initiative (#1 P20 RR020173-01) for a mouse model of myocardial injury, assessment of the response to injury, and the development of heart failure. Dr. Tsuda’s primary interest is in the role of the extracellular matrix proteins in the signal transduction that induces heart failure. Dr. Tsuda has established molecular biologic and physiologic tools to evaluate the heart’s response and recovery to acute injury in vivo and developed an in vitro cell culture system to test the specific hypotheses being addressed. Dr. Tsuda currently has three grant-supported research projects: 1) a project in the statewide INBRE grant, 2) a pilot DHSA grant in collaboration with University of Delaware regarding the role of JAM-A in heart failure, and 3) a Nemours Research Grant to study a specific role of extracellular matrix proteins in transforming growth factor (TGF) activation during the development of cardiac hypertrophy and fibrosis, which is being transitioned to INBRE state match funds.

Dr. Tsuda’s mouse model can be widely generalized to many different disease states. This offers the opportunity for collaboration across Nemours and with other institutions in studying mechanisms of cardiac function and heart failure. The COBRE grant has long-term implications for the Cardiac Center. Dr. Derby is collaborating with Dr. Akins and biomedical engineers at the University of Delaware to develop a long-acting form of low molecular weight heparin utilizing advanced biomaterials. This research, funded by Nemours, will benefit pediatric patients who require long-term anticoagulation. Dr. McCulloch is also the primary investigator of a collaborative effort producing a computer model for continuous, real-time assessment of systemic oxygen delivery in newborns with single ventricle physiology.

Congenital heart malformations are the most common birth defect and remain one of the leading causes of infant death. Although surgical procedures have done much to improve the medical outcome of children affected with cardiac malformations, our understanding of their genetic/environmental basis has lagged significantly behind. This is due to the occurrence of genetic heterogeneity, reduced penetrance, and variable expressivity in these diseases. The advent of molecular genetics and development of animal models with genetically-induced cardiac malformations have provided powerful tools in which to address the basis for human malformations. Through their research, Drs. Funanage and Pizarro seek to gain an understanding of the molecular basis for hypoplastic left heart syndrome (HLHS), which is the fourth most frequent cardiac malformation and is universally fatal without surgical intervention. A better understanding of the etiology of HLHS, together with an understanding of the pathways involved in normal cardiac development and function, will most likely lead to further improvement in medical and surgical outcomes. The central hypothesis is that HLHS results from mutations in cardiac transcription factors whose expression is both temporally and spatially regulated in the developing heart. To date, mutations have been identified in two transcription factors, TBX5 and NKX2.5.