Cardiac derived (CPCs) and bone marrow derived (BMCs) stem cells containing the cell marker c-kit have the potential to differentiate into cardiac myocytes. These cells have been used to improve cardiac repair and function after myocardial infarction in both animal models and clinical trials. Calcium influx through L-type calcium channels (LTCCs) plays an important role in inducing these cells to commit to the cardiac lineage and form new myocytes. The 22a subunit of LTCCs is responsible for trafficking of the protein to the plasma membrane and sarcolemma. The B2a subunit has been effectively upregulated in a rat myocytes using an adenovirus construct. We will determine if upregulation of the B2a subunit via an adeno-associated virus construct in CPCs and BMCs results in increased density and open probability of LTCCs. We will determine through co-culture with neonatal rat ventricular myocytes, if this upregulation of calcium influx causes increased commitment to the cardiac lineage. A murine acute myocardial infarction model will be established and these cells will be injected into the infarct border zone. We will determine if increased calcium influx results in enhanced engraftment of CPCs and BMCs into ischemic myocardium and whether the cells have improved regenerative capacity. Cardiac function will be measured using echocardiogram and pressure- volume measurements. Once proof of concept studies has been done in mice and if efficacy is shown in the 22a infected stem cells, they will also be tested in a porcine model.

Public Health Relevance

As ischemic heart disease continues to be the number one killer in the world, it is imperative that the scientific community continues to look for novel therapies. My research will determine if functional cardiac tissue can be regenerated using stem cells that have been genetically modified to have increased calcium influx. This will lay the foundation for a novel therapy to be developed for patients suffering from ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL110687-02
Application #
8322986
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2011-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$55,670
Indirect Cost
Name
Temple University
Department
Surgery
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122