Congenital heart disease, the most common birth defect, is frequently associated with deficient heart muscle, leading to heart failure. Currently, the only way to replace heart muscle cells, cardiomyocytes, is through heart transplantation. Regenerative therapies would transform the treatment of congenital heart disease and save many lives. We study the mechanisms of cardiomyocyte proliferation with the aim of increasing this process therapeutically. We have previously demonstrated that extracellular factors can be used to stimulate cardiomyocyte proliferation, leading to improved myocardial structure and function in animal models of heart failure. The clinical translation of this innovative approach requires understanding of how cardiomyocytes are able to perform two completely different tasks: contraction of myofibrils and cell division. We have shown that during cell division cardiomyocytes divide their contractile apparati, which consist of myofibrils, but the detailed mechanisms are not understood. It has been shown that myofibril formation and cardiomyocyte cytokinesis are controlled by mechanisms involving p38? mitogen-activated protein kinase (MAPK), but the role of p38? in myofibril disassembly remains unknown. Our preliminary data indicate that cardiomyocyte cell cycle activity in humans is highest in infants, suggesting that regenerative cardiomyocyte proliferation may be most effectively stimulated in this age group. We will therefore perform our investigations in neonatal animals. We hypothesize that myofibril disassembly in proliferating neonatal cardiomyocytes is a conserved, multi-step process that is controlled by a mechanism involving p38? MAPK and is associated with brief reduction of cardiomyocyte contractile function.
In Aim 1 we will define and characterize the disassembly process.
In Aim 2, we will modify p38 signaling and determine the effects on myofibril disassembly.
In Aim 3, we will determine the effect of myofibril disassembly on cardiomyocyte function in the intact heart. The results of this research should increase the translational potential of regenerative strategies that stimulate cardiomyocyte proliferation.
Congenital heart disease, the most common birth defect, is frequently associated with deficient heart muscle, leading to heart failure. Currently, the only way to replace heart muscle cells, cardiomyocytes, is through heart transplantation. The proposed research will advance the scientific basis for regenerative therapies to treat patients with congenital heart disease. These new therapies should improve the lives of many patients who have heart failure as a complication of congenital heart disease.
|Yester, Jessie Wettig; Kühn, Bernhard (2017) Mechanisms of Cardiomyocyte Proliferation and Differentiation in Development and Regeneration. Curr Cardiol Rep 19:13|
|Ganapathy, Balakrishnan; Nandhagopal, Nikitha; Polizzotti, Brian D et al. (2016) Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth. PLoS One 11:e0155456|
|Polizzotti, Brian D; Ganapathy, Balakrishnan; Haubner, Bernhard J et al. (2016) A cryoinjury model in neonatal mice for cardiac translational and regeneration research. Nat Protoc 11:542-52|
|Polizzotti, Brian D; Ganapathy, Balakrishnan; Walsh, Stuart et al. (2015) Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. Sci Transl Med 7:281ra45|
|Dueck, Hannah; Khaladkar, Mugdha; Kim, Tae Kyung et al. (2015) Deep sequencing reveals cell-type-specific patterns of single-cell transcriptome variation. Genome Biol 16:122|
|Senyo, Samuel E; Lee, Richard T; Kühn, Bernhard (2014) Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res 13:532-41|
|Burns, Kristin M; Byrne, Barry J; Gelb, Bruce D et al. (2014) New mechanistic and therapeutic targets for pediatric heart failure: report from a National Heart, Lung, and Blood Institute working group. Circulation 130:79-86|
|Zhang, Cheng-Hai; Kühn, Bernhard (2014) Muscling up the heart: a preadolescent cardiomyocyte proliferation contributes to heart growth. Circ Res 115:690-2|
|Parodi, Emily M; Kuhn, Bernhard (2014) Signalling between microvascular endothelium and cardiomyocytes through neuregulin. Cardiovasc Res 102:194-204|
|Khaladkar, Mugdha; Buckley, Peter T; Lee, Miler T et al. (2013) Subcellular RNA sequencing reveals broad presence of cytoplasmic intron-sequence retaining transcripts in mouse and rat neurons. PLoS One 8:e76194|
Showing the most recent 10 out of 16 publications