Myocrdial biology has been transformed by recognition of the role played by cardiac progenitor cells (CPC) in repair and regeneration following pathological injury as well as their participation in normal cardiac homoestsis, remodeling, and aging. The initial period of this MERIT award focused upon two key regulatory proteins that our group identified as key players in CPC biology: Notch and nucleostemin. Since our initial descriptions of these signaling proteins in the myocardial context both have been studied and integrated into the fabric of cardiovascular literature. This MERIT award extension period will take our understanding of Notch and nucleostemin to a higher level by defining connections between these molecules, canonical pathways in myocardial regulatory signaling, and involvement in the biology of CPC. The significance of this proposal is novel information that can be applied directly toward the manipulation of CPC to enhance myocardial repair and regeneration as well as understanding pathological mechanisms resulting from CPC dysfunction. Innovative aspects of this proposal include the use of unique reagents to manipulate Notch and nucleostemin activity through use of inducible constructs, silencing vectors, and observation of activity through genetically engineered reporters both in cultured cells and transgenic mice.
Specific aims are 1) Notch signaling potentiates cardiac progenitor differentiation into cardiac lineages in vitro and in vivo, 2) Notch signaling facilitates repair and regeneration of damaged mouse myocardium in vivo, S) Pim-1 mediated c-Myc stabilization induces nucleostemin that enhances regenerative potential and survival of cardiac progenitor cells, 4) nucleostemin regulates stem and progenitor cell pluripotency, and 5) elevated nucleostemin expression triggers hypertrophic signaling and enhances regenerative potential in the heart. The impact of the proposal will be advancing the use, manipulation, and control of CPC biology to facilitate myocardial reparative processes as well as explaining the underlying biology of myocardial responses to injury, adaptive remodeling, and aging. As cardiovascular stem cell biology enters the clinical arena it is essential to acquire mechanistic understanding to achieve optimal results.
Cardiovascular disease remains a major cause of morbidity and mortality in the United States and places a substantial economic burden upon society. This proposal seeks to understand mechanisms responsible for repair and regeneration of the damaged heart that are by nature not designed to replace acute injuries. Successful completion of the proposed aims will provide significant insight for how reparative and regenerative processes will successfully be implemented as clinically-relevant treatments for heart disease.
|Samse, Kaitlen; Hariharan, Nirmala; Sussman, Mark A (2016) Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase. Pharmacol Res 103:13-6|
|Broughton, Kathleen M; Sussman, Mark A (2016) Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps. Circ Res 118:867-80|
|Orogo, Amabel M; Gonzalez, Eileen R; Kubli, Dieter A et al. (2015) Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival. J Biol Chem 290:22061-75|
|Hariharan, Nirmala; Sussman, Mark A (2015) Cardiac aging - Getting to the stem of the problem. J Mol Cell Cardiol 83:32-6|
|Nguyen, Nathalie; Sussman, Mark A (2015) Rejuvenating the senescent heart. Curr Opin Cardiol 30:235-9|
|Hariharan, Nirmala; Quijada, Pearl; Mohsin, Sadia et al. (2015) Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J Am Coll Cardiol 65:133-47|
|Quijada, Pearl; Sussman, Mark A (2015) Circulating around the tissue: hematopoietic cell-based fusion versus transdifferentiation. Circ Res 116:563-5|
|Quijada, Pearl; Hariharan, Nirmala; Cubillo, Jonathan D et al. (2015) Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment. J Biol Chem 290:25411-26|
|Samse, Kaitlen; Emathinger, Jacqueline; Hariharan, Nirmala et al. (2015) Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells. J Biol Chem 290:13935-47|
|Gude, Natalie; Joyo, Eri; Toko, Haruhiro et al. (2015) Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells. Basic Res Cardiol 110:29|
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