Fellow, Pediatric Cardiology University of Rochester School of Medicine and Dentistry 21 saxony road, pittsford, New York, United States
Background: Mitochondrial chaperone protein cyclophilin D (CypD), plays an important role in cardiac differentiation, proliferation, and function both in fetal and early neonatal life through its effect on closure of the mitochondrial permeability transition pore (PTP). Deletion or inhibition (cyclosporin A, NIM811) of CypD or activation of the PTP (BZ-423) can affect cardiomyocyte proliferation and function. Objective: Determine the effects of manipulation of CypD and the PTP on cardiac function and regeneration in neonatal mice. Design/Methods: First, wild type (WT) and CypD -/- mice are injected with CsA, NIM811, BZ-423, or vehicle and perform echocardiography to assess cardiac function daily from postnatal day (P)1 to P6. Preliminary data suggest that deletion or inhibition of CypD increased cardiac function compared to controls in the first few days of life, but this effect is not apparent by P7. Second, WT and CypD +/- and -/- mice undergo cardiac cryoinjury at P1 using a liquid nitrogen-cooled probe. Following surgery, survival rates are compared in different mice genotypes, and echocardiograms are performed on post-op days 7 and 28 when mice are euthanized and hearts are removed for histology to assess the regenerative response. Preliminary data suggest that WT mice have increased regeneration and less fibrosis compared to CypD +/- and -/- mice. For echocardiography, we will analyze at least 11 animals from different litters for each group based on a power analysis using a power of 0.8, type I error of 0.05, estimated ejection fraction means of 80 and 90 % for WT and CypD -/- mice, and a standard deviation of 9% from preliminary data. For other analyses, we will analyze at least 5 independent replicates. Data will be analyzed for I) the presence of time effects, which differ by treatment group; ll) the presence of time effects but no difference between treatment groups; lll) treatment group differences, independent of time.
