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Dean Li

Associate Professor of Medicine and of Oncological Sciences

B.A. University of Chicago

M.D. Washington University

Ph.D. Washington University

Research

References

dean@hmbg.utah.edu

 

Research

Our laboratory is focused on understanding the pathogenesis of vascular disease. We have generated and characterized murine models for three human vascular diseases: supravalvular stenosis (SVAS), hereditary hemorrhagic telangiectasia (HHT), and cerebral cavernous malformations (CCM). Mutations in the elastin gene are responsible for SVAS and we demonstrated that elastin plays a critical role in arterial morphogenesis, regulating vascular smooth muscle cell migration, proliferation and differentiation (J. Clin. Invest. 102: 1783-1787: Nature 393:276-280). Mutations in the genes encoding receptors for the TGF Beta superfamily of growth factors, activin receptor-like kinase 1 and endoglin, are responsible for HHT (Science 284: 1534-1537: Nature Genetics 26: 328-3310. These genes are critical for endothelial cells to functionally distinguish themselves as arteries or veins. Targeted ablation of these genes in mice causes arteries and veins to sprout from the central axial network and fuse with one another. One gene responsible for CCM is krit 1. Our studies indicate that mice lacking krit 1 fail to maintain distinct arterial and venous identities due to disruption of a notch-mediated pathway (Development 131(6):1437-48). We will continue to focus on generating murine models of cardiovascular disease. Recently, it has been demonstrated that mutations in the second gene, CCM2, causes cerebral cavernous malformations. We are in the process of characterizing mice lacking these genes.

As a direct result of studying these murine models of vascular disease, we have embarked on a new direction. We identified new ligands and receptors that are responsible for endothelial and vascular smooth muscle cell biology. These gene families are related to those that mediate neural guidance. Netrin is an extracellular cue that attracts axons, while slit is a repulsive cue that axons avoid. In vitro, ex vivo, and in vivo experiments indicate that these proteins modulate angiogenesis in an analogous manner to neural outgrowth. We are characterizing the function of these genes in vascular development using gene targeted mice and zebrafish genetics.

Finally, we are very interested in applying our knowledge of vascular biology and development to the treatment of human diseases. In our work with elastin, we engineered an elastin sheath-stent prototype and showed that it significantly reduces coronary restenosis in a porcine model (Development. 130(2):411-420). In collaboration with interventional cardiology and other pharmaceutical and biotechnology firms, we are currently redesigning the delivery of elastin biomaterials to the vascular wall to enhance their ease of use. We are also investigating the role of the new angiogenic factors related to neural guidance family of proteins in tumor angiogenesis and ischemic vascular diseases. Thus, our laboratory provides a fertile training environment for those interested in either basic vascular development or the practical application of this new scientific knowledge.

Netrin-1 stimulates angiogenesis (A) Quantitative analysis of chick chorioallantoic membrane assays. The average number of vessels surrounding the implanted mesh is calculated and converted to fold. (B) Representative photographs for each factor.

References