Cardiac Repair and Regeneration Research Unit | Heart and …

DEB Laboratory

Research Aims: We broadly investigate mechanisms of cardiac repair and regeneration and in particular study the interface of scar forming cells and cardiac progenitors in regulating a cardiac injury response. We use a variety of genetic, molecular and physiologic approaches to study how the outcome of a repair response can be manipulated to minimize scarring and enhance cardiac function. Main projects in the lab are summarized below:

The heart is unable to regenerate heart muscle after a heart attack and lost cardiac muscle is replaced by scar tissue. Scar tissue does not contribute to cardiac contractile force and the remaining viable cardiac muscle is thus subject to a greater hemodynamic burden. Over time, the heart muscle eventually fails leading to the development of heart failure and 500,000 patients are diagnosed annually in the United States with heart failure. Thus the inability of the heart to regenerate cardiac muscle, coupled with a predominant fibrotic injury response remain major fundamental obstacles to treating heart disease.

Our laboratory studies the interface of cardiac fibroblasts (scar forming cells) and cardiac progenitors in determining how a cross talk between these cells regulates cardiac repair. We use murine models of cardiac injury and use a variety of fate mapping and conditional knockout strategies to alter specific genes at specific time points after injury to investigate our questions. We study the Wnt signaling pathway, a family of 19 closely related proteins that play key roles in organogenesis, wound healing and cancer. We have recently demonstrated that Wnt1, a Wnt known to play important roles in the development of the central nervous system plays an important role in regulating a fibrotic injury response in the heart. Using transgenic and conditional knock out strategies, we aim to alter the fibrotic repair response of the heart to enable regeneration.

The second area of investigation in or laboratory is to understand the biology of the epicardium and how it regulates wound healing in the adult heart. The epicardium is a single layer of epithelial cells, that surrounds the heart. Although the epicardium is critically important for cardiac development, little is known about the function of the epicardium in the adult heart. We have recently demonstrated that the epicardium undergoes epithelial-mesenchymal-transition in a Wnt dependent manner after cardiac injury and generates cardiac fibroblasts that reside in the subepicardial space and contribute to cardiac fibrosis. We have observed that epicardial EMT is a critical repair response of the heart and disruption of epicardial EMT worsens cardiac function after acute cardiac injury. The molecular regulation of epicardial EMT, identification of precursors in the epicardium that give rise to cardiac fibroblasts and its role in wound healing form another major focus in our laboratory.

Calcification of the heart is a predominant phenotype of the aging heart and pathologic calcification predisposes to cardiac disease. For instance, calcification of the conduction system in humans causes slowing of conduction and heart blocks, while calcification of the valves leads to stiffening of the valve leaflets, and obstruction or regurgitation of blood across the valves secondary to defective coaptation of valve leaflets. The origins of the cells contributing to cardiac calcification and mechanisms regulating calcium deposition remain ill understood. Using human heart valves (obtained during surgical replacement of calcific heart valves), we isolate and study progenitor populations that can contribute to cardiac calcification. We also have murine models of calcification that we use to obtain fate maps about potential progenitor populations contributing to cardiac calcification and study mechanisms driving progenitors to adopt an osteoblast (calcium forming cell) fate. This project allows the interrogation of mechanisms in both murine models and human tissue.

Personnel:

Publications:DEB_LAB_PUBS

Contact:Arjun Deb, MDadeb@mednet.ucla.eduOffice: (310) 825-9911

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Cardiac Repair and Regeneration Research Unit | Heart and ...