Current Clinical Projects
Members of Theme Six are developing stem cell and cellular reprogramming strategies to treat cardiovascular diseases such as infarction in situ. The goal is to use viral vectors to induce transdifferentiation of cardiac fibroblasts and myofibroblasts into functional cardiomyocytes in situ in a patient’s heart. We are modeling and developing the processes in rats, pigs, and in human cardiac fibroblasts. The hope is to have options available for clinical trials within 3-5 years.
Current Basic Research Project(s)
Members of Theme Six are involved in research aimed at improving heart function after different types of injury and in particular the devastating loss of heart muscle after myocardial infarction. One current approach is to investigate gene pathways, many of which are important in heart development, that enhance the ability of cardiac muscle to respond to injury. Recent exciting findings have shown that manipulations of specific genetic pathways, such as the Hippo pathway, enhance heart repair. Current investigations in this area include uncovering the molecular mechanisms underlying improved heart repair in order to develop novel therapies.
Another exciting approach involves in vivo reprogramming of cardiac fibroblasts into cardiac muscle as a way to enhance heart function after ischemic injury. This novel method was inspired by the observation by Yamanaka that fibroblasts can be reprogrammed to pluripotent cells in cultured cells. Important recent work has shown that providing a cocktail of factors to cardiac fibroblasts results in conversion of those fibroblasts into cardiac muscle. Current efforts are directed at improving the efficiency of in vivo reprogramming with the goal of using this approach in therapy, recognizing that use of this strategy in human cells will likely be more challenging than in rodent and other non-human strains. The combination of angiogenic pretreatment of scar with this strategy appears to be critical to its success.
Key Publications 2014
Sadek HA, Martin JF, Takeuchi JK, Leor J, Nei Y, Giacca M, Lee RT. Multi-investigator letter on reproducibility of neonatal heart regeneration following apical resection. Stem Cell Reports. 2014; 3(1): 1.
Yen ST, Zhang M, Deng JM, Usman SJ, Smith CN, Parker-Thornburg J, Swinton PG, Martin JF, Behringer RR. Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes. Dev Biol. 2014; 393(1): 3-9.
C. Thomas Caskey, M.D. - FACP, FRSC Schizophrenia disease genes
Katarzyna Cieslik, Ph.D. - Cardiac mesenchymal progenitors
Austin Cooney, Ph.D. - Nuclear receptor regulation of embryonic stem cell function
Thomas Cooper, M.D. - Alternative splicing in cardiac development and disease
Mary Dickinson, Ph.D. - Role of fluid-derived mechanical forces in vascular remodeling and heart morphogenesis
Mark Entman, M.D. - Molecular mechanisms of cardiac injury and repair, inflammatory signaling
Charles Fraser, M.D. - Congenital heart surgery outcomes, bioengineering and assist devices
Peggy Goodell, M.D. - Hematopoietic stem cells, epigenetic modifications
Jeffrey Jacot, Ph.D. - Regenerative therapies for congenital heart disease
Sandra Haudek, Ph.D. - Circulating monocytic fibroblast precursors, cardiac hypertrophy
George Noon, M.D. - Transplant and assist devices
JoAnn Trial, Ph.D. - Origins of fibroblasts in cardiac injury healing
Peter Tsai, M.D., FACS - Custom-fenestrated endovascular stents to repair aortic transections or aneurysms