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Project 2: Molecular Mechanisms of Myocardial Regeneration and Stem Cell Biology
Overview
Heart failure is a common and deadly disease. The only definitive therapy for advanced heart failure is orthotopic heart transplantation. Due to limited organ availability, the goals of Project 2 are directed toward an enhanced understanding of the regulatory factors such as myocardin that promote stem cells to adopt a cardiac cell fate and an enhanced understanding of the contribution of resident and extracardiac stem cells for myocardial regeneration in the adult mouse and human heart. We will decipher the mechanisms whereby myocardin regulates cardiac development and identify regulatory factors and signaling systems that govern myocardin activity and expression as a platform for cell-based cardiovascular therapies. We hypothesize that the adult human heart contains a resident cardiac stem cell population that expresses ABCG2 (a molecular marker for the SP cell population) and this cardiac stem cell population participates in limited myocardial repair. In response to a severe insult we hypothesize that extracardiac stem cells are recruited from other tissues including the bone marrow to complement the resident cardiac stem cells and partially repair the adult heart. This study tests the overall hypothesis that intrinsic cardiac stem cells and migrating extracardiac stem cells participate in the repopulation and regeneration of the adult myopathic heart and that their acquisition of a differentiated cardiac phenotype relies on normal developmental control mechanisms. The focus of Project 2 is directed toward an enhanced understanding of stem cell biology, cardiogenesis and myocardial regeneration. The results of the basic science studies will serve as a platform for cell based clinical strategies to promote myocardial regeneration. Specific Aim #1: Our original Specific Aim #1 is: To identify transcription factors and signaling molecules that modulate the activity of myocardin in cardiac and smooth muscle cells and to use this information to program embryonic stem cells to adopt a cardiac or smooth muscle cell fate. We have refined our specific aim as follows: Optimize small molecules with cardiogenic activity and program embryonic stem cells to adopt a cardiac fate using small molecule libraries. Specific Aim #2: To define the regenerative capacity of the adult heart. Specific Aim #3: To define the capacity of extracardiac stem cells to contribute to myocardial regeneration. As recommended by the Scientific Review Committee, we have deleted this specific aim. |
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Eric Olson, Ph.D.
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