Cell therapy is promising for repair of damaged myocardium. But moderate and variable functional benefits in clinical trials emphasize the need for a better understanding of therapeutic mechanisms and for specific imaging techniques which provide insights beyond cardiac function. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium, limiting therapeutic efficacy and providing a potential explanation for the variability of functional benefits. The myocardial microenvironment is considered to be a critical contributor to successful cell engraftment and constitutes a suitable target for molecular imaging. In this proposal, we aim at developing strategies to facilitate successful stem cell engraftment. Our central hypothesis is that molecular-targeted nuclear imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims. Quantitative nuclear imaging techniques will be employed to characterize both, myocardial environment, as well as stem cell engraftment in a rat model of myocardial infarction. Therapy outcome will be defined by serial echocardiography and histologic workup.
Aim 1 will define the role of tissue perfusion, metabolism and viability in the target area of stem cell delivery, for successful engraftment of cardiac-derived stem cells, an innovative cell type with documented regenerative potential.
Aim 2 will investigate the role of expression of the adhesion molecule 1v23 integrin in the target area, as determined by molecular imaging, for successful cardiac stem cell engraftment.
In aim 3, cardiac stem cells as a newer cell type will then be compared with the longer established mesenchymal stem cells under conditions of optimal imaging-defined microenvironmental conditions. These studies will provide unique new insights into the contribution of the biologic environment to the success of stem cell based myocardial regeneration. More importantly, they will also provide imaging techniques which may assist in therapeutic decision making by guiding the timing and regional targeting of cell delivery. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology.

Public Health Relevance

Project Narrative / Relevance Cardiac stem cell therapy is considered to be a very promising approach for repair of damaged myocardium, but the benefit in clinical trials is currently still variable. In this proposal, molecular imaging techniques are introduced which aim at improving cell therapy by providing information about myocardial microenvironmental conditions which are most suitable for stem cell engraftment. Such biologic imaging strategies have the potential to guide individual therapeutic decisions, and are thus highly relevant to optimize the benefit of stem cell therapy in the clinical management of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092985-03
Application #
8207204
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Adhikari, Bishow B
Project Start
2010-01-15
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$489,163
Indirect Cost
$187,667
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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