Heart Regeneration and Graft Associated Arrythmia in Large Mammals

Abstract

Despite ongoing improvements in the management of cardiac disease, patients with severe acute myocardial infarction (AMI) often progress to end-stage congestive heart failure, which remains one of the most significant problems in public health. From molecular

and cellular perspective, heart failure is caused by the loss of cardiomyocytes--the fundamental contractile units of the heart. Mammalian cardiomyocytes (CM) exit the cell cycle shortly after birth and, consequently, cardiomyocytes in the hearts of adult

mammals cannot proliferate in response to injury. However, we have shown that when MI was induced in the hearts of newborn pigs on postnatal day 1 (P1), the animals recovered with significantly decreased scar size and residual fibrosis in the myocardium, and that the repair process was accompanied by increases in the expression of markers for cell-cycle activity in cardiomyocytes. Furthermore using a double injury model, when apical resection surgery (AR) was performed on P1 and AMI was induced on postnatal day 28 (P28) in the same large mammal, cardiomyocytes proliferated in response to the second injury and regenerated the damaged myocardium on P56; thus, AR on P1 extended the time window of cardiomyocyte proliferation and cardiac repair through at least to P28. We have also developed a novel cell-cycle-specific bioinformatics algorithm (CSA) for analyzing single-nucleus RNA sequencing (snRNAseq) data, which enables us to more precisely evaluate cell-cycle activity in subpopulations of cardiomyocytes. We have recently established a novel Cardiomyocyte-specific Modified mRNA Translation System (CM-SMRTs) for gene targeting, which was inspired by the effectiveness and safety of mRNA-based vaccines against SARS-CoV-2. The CM SMRTs based delivery system could efficiently target the key transcription regulator(s) and "turn-back-the-clock" of CM cell cycle, and address an unmet clinical need by providing an efficient and titratable method for transiently modifying gene expression

specifically in cardiomyocyte.

Participants will be able to discuss and explain the current understanding of the major roadblocks in myocardial regeneration, and the potential approaches to overcome these roadblocks. Participants will also share their knowledge and interests in pursuing novel

applications in this emerging field of modRNA therapeutics.

Bio

Jianyi "Jay" Zhang, M.D., Ph.D., is an international leader in myocardial bioenergetics, and cells/cell-products for cardiac repair. He is a tenured Professor of Medicine and of Engineering; T. Michael and Gillian Goodrich Endowed Chair of Engineering Leadership; and the Chair of the Department of Biomedical Engineering (BME). He came to UAB in October 2015 after he was chosen in a national search to lead the UAB BME department from the University of Minnesota Medical School, where he was the Engdahl Family Foundation Chair in Cardiovascular Regenerative Therapies, in addition to being a tenured professor of medicine, of biomedical engineering, of electrical engineering, and computer engineering. Zhang earned his M.D. from Shanghai Medical University in 1983 and his Ph.D. in biomedical engineering from the University of Minnesota in 1992. Since his arrival at UAB, the Department of Biomedical Engineering rose to the rank of top 10th in the nation in NIH funding (Blue Ridge Institute) in the past 7 years consecutively under Zhang's leadership. Dr. Zhang has mentored 21 PhD students earned their PhD degree from University of Minnesota or UAB. Dr. Zhang's research interests include iPS technology, heart failure, cell-products for cardiac repair. He is currently the PI of NIH multiple R01 grants, one NIH U01 grant, and one PPG that through 2027. The Zhang lab has published >200 papers in high impact journals including Circulation, Circulation Research, Cell Stem Cell, Science Translational Medicine research; he has trained more than 90 trainees, and led 18 students earning their Ph.D. He is Charter Reviewer on NIH study sections (through 2026); editorial board member for Circulation, Circulation Research, and others.