The Transplantation and Immunology Research Network (TIRN), an American Society of Transplantation (AST) program, has awarded Duke Anesthesiology’s Dr. Anne Cherry a one-year, $50,000 AST TIRN Basic Science Faculty Development Research Grant for her proposal titled, “Interface of Mitochondrial Dysfunction and Immune Activation in Heterotopic Mouse Heart Transplant.”
Primary graft dysfunction (PGD) after cardiac transplant occurs in about 7.5 percent of recipients; there is concern that the rate is increasing due to a) extension of ischemic time to facilitate organ distribution and b) increasing use of high risk donor organs due to increasing mismatch in organ demand vs. availability. Graft dysfunction is a devastating complication, resulting in prolonged post-transplant hospitalization (often requiring invasive mechanical circulatory support or re-transplant) and 35 percent one-year mortality.
The long term goal of Dr. Cherry’s research is to identify and manipulate signaling targets that control the interface between impaired mitochondrial quality control after ischemia/reperfusion (I/R) injury and inflammatory activation in PGD to a) improve donor selection (prediction of PGD), b) implement pre-organ harvest donor interventions to stimulate mitochondrial quality control pathways, and c) intervene by specifically targeting key modulators of the mitochondrial-inflammatory interface to prevent excessive immune activation.
Through this research, Dr. Cherry aims to 1) characterize the impact of deficits in mitochondrial function and recovery on PGD in a syngenic transgenic heterotopic mouse heart transplant model and 2) characterize subsequent inflammatory activation attributable to those pre-existing mitochondrial regulation deficits acutely (24 hours) and at mid- to longer-term time points (7 and 21 days). She will serially investigate and compare changes in mitochondrial structure/distribution (electron microscopy); oxidative damage, cell death and fibrosis; molecular mitochondrial quality control markers; and graft function (echocardiography) will help illustrate the PGD phenotype in this model. Differences in the temporal course (particularly focused on macrophage phenotypes), magnitude, cellular composition, and functionality of the immune phenotype for PGC-1ɑ +/- vs. WT grafts will be evaluated using histology, markers for neutrophil infiltration, and flow cytometry characterization of both serum and graft infiltrates. Together, these aims will allow identification and, most importantly, manipulation of key modulators of the mitochondrial-inflammatory interface in cardiac transplant patients.
Overall, this investigation into the interaction of mitochondrial quality control and oxidative stress with inflammatory injury will also translate to patients with graft dysfunction of other transplanted organs and to ischemia/reperfusion injury in other pathologic processes (i.e. myocardial infarction). Dr. Cherry will use the novel mechanisms to identify new interventions to modulate I/R injury and graft dysfunction, promote recovery, and prevent consequent immune activation.
The AST is the largest transplant organization in America, dedicated to advancing the field of transplantation and improving patient care by promoting research, education, advocacy and organ donation. Dr. Cherry, assistant professor of anesthesiology in Duke’s Cardiothoracic Anesthesia Division, will accept this grant award at the AST Excellence in Transplantation Reception at the 2017 American Transplant Congress in Chicago on May 1. Her research for this project will begin on July 1.