David W. Griggs, Ph.D. » Investigators

Cardiovascular Research Interests:

Primary area of research:

• Biochemical mechanisms mediating angiogenesis, fibrosis, and vaso-occlusion

Related areas of research:

• Retinopathies and macular degeneration
• Sickle cell disease
• Tumor vascularization

Summary of cardiovascular research:

A particular area of longtime interest to my lab has been the role that the integrin family of proteins plays in regulating key processes relevant to both normal physiology and disease, and the development of low-molecular-weight synthetic chemical compounds capable of selectively modulating these functions. Of the 23 integrins expressed in humans, approximately one-third bind to a specific amino acid motif, arg-gly-asp (RGD), contained within the sequence of the integrin’s cognate protein ligand. RGD-binding integrins are known to mediate platelet aggregation required for blood clotting, the excess adherence of red blood cells to activated endothelium in the context of sickle cell disease, and new blood vessel formation associated with tissue hypoxia and wound healing. They also have critical functions in the temporo-spatial activation of the master cytokine TGFβ in various tissue environments, which in turn regulates fibrosis, inflammation, and the immune response.

In previous research studies, we showed that small molecule peptidomimetic compounds based on the RGD sequence were capable of highly potent inhibition of integrins such as αvβ3, α5β1, and αvβ6. Furthermore, several orally bioavailable integrin antagonists effectively blocked angiogenesis, tumor growth, and metastasis in animal models. Current studies are directed at expanding our understanding of how specific integrins mediate pathologic events implicated in a variety of orphan diseases, many of which have a significant vascular component. We employ a variety of technical disciplines, including synthetic medicinal chemistry, biochemical and cell-based functional assays, and in vivo pharmacology with the goal of either advancing existing drugs for new clinical indications or discovering new drugs that can be externally partnered for development.