David W. Griggs
Ph.D., University of Illinois at Urbana-Champaign (Microbiology)
Department: Director of Cellular & Molecular Biology - Center for World Health & Medicine
Adjunct Assistant Professor, Pharmacology & Physiology
Academic Rank: Director (Cell and Molecular Biology) and Adjunct Assistant Professor
Phone: 314-977-5138 Fax: 314-977-5220
Lab Web Page Links: www.cwhm.org
Primary Area of Cardiovascular Research Interest
- Biochemical mechanisms mediating angiogenesis, fibrosis, and vaso-occlusion
Related Areas of Cardiovascular Research Interest
- Retinopathies and macular degeneration
- Sickle cell disease
- Tumor vascularization
Summary of Cardiovascular Research Interest
The Center for World Health & Medicine (CWHM) conducts highly collaborative preclinical research to identify and advance new therapeutic agents for rare and neglected diseases. A particular area of longtime interest to me 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 research conducted as part of our former industrial drug-discovery programs at Searle, Pharmacia, and Pfizer, 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 in this area at the Center for World health & Medicine 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 which can be externally partnered for development.