Long Term Research Aims

To investigate and treat cardiovascular disease through modulation of gene expression.

Mid-Term Research Aims

• Identify novel mechanisms of vascular disease.
• Develop novel therapeutic strategies.
• Test vectors in relevant animal models.
• Design clinical gene transfer studies.

Approach

To reach the aims as outlined above, we have developed three specific areas of interest in the broad field of cardiovascular disease. Within each aim, we are identifying new targets and developing vectors with therapeutic aims. The first of these aims is to inhibit thrombosis at the sites of vascular injury. We believe that an imbalance exists within diseased vessels which predisposes towards the formation of thrombosis. We have identified a key player, tissue factor pathway inhibitor that although expressed in diseased vessels, is expressed in relatively minor amounts compared to its protagonist tissue factor. We have developed genetically modified mice and methods of genetic overexpression to study these diseased states.

In addition, we have developed a vascular approach to the treatment of heart failure by overexpressing chimeras of natriuretic peptides. NPs are vasoactive, natriuretic, diuretic, lusitropic hormone which the heart expresses. These peptides have beneficial effects in early stages of heart failure, and we have sought to overexpress it using nonviral and viral vectors from the myocardium. Future work will be aimed at optimizing delivery strategies to reach levels that will be therapeutic in the prevention of heart failure. We are pursuing development of nonviral mechanisms of gene transfer into the heart and vasculature. These include cellular approaches as well as using physical methods such as ultrasound.