Dean Li
Distinguished Professor of Medicine and of Oncological Sciences and of Human Genetics
B.A. University of Chicago
M.D. Washington University
Ph.D. Washington University
Dean Li's PubMed Literature Search
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. There are three genes. Our lab has used knock out technology to define the roles of two of the genes and have established the critical role of the CCM genes in vascular stabilization. (Development 131(6):1437-48: Nat Med 15(2):177-84). These discoveries have allowed us to discover a new signaling cascade that regulates cell shape and junctions.
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 vascular regeneration and stability. Netrins and its receptors stimulate angiogenesis with a unique ability to promote neurovascular regeneration in conditions such as diabetes (Development135:659-67; Science 313:640-4). Slits enhance vascular stability and inhibit pathologic angiogenesis and endothelial hyperpermeability via an endothelial specific receptor Robo4 (Nat Med. 14(4):448-53). We have shown that activating this pathway is effective in animal models of age related macular degeneration and diabetic retinopathy. Since cancer and acute inflammatory diseases are characterized by excessive vascular growth or leakage, we are exploring the extent that Robo4 signaling can be applied to treat these diseases. Little is know about the molecular basis of these signaling cascades in neural or vascular biology. Our studies dissecting these pathways have led to new targets for high-throughput screens for small molecule modulators that are effective in regulating vascular regeneration and stability in animal models of human diseases.
Our laboratory uses mice and zebrafish as genetic model systems and incorporates biochemical signaling and cell culture studies. The overarching goal is to impact either our understanding and/or treatment of human diseases. We seek to drive our projects toward medical application by focusing on the animal work required to support an application to the FDA for phase I clinical trials. In addition to scientific discovery, trainees formulate patent applications, grant proposals and manuscripts.
References
1. Jones CA, Nishiya N, London NR, Zhu W, Sorensen LK, Chan A, Lim CJ, Chen H, Zhang Q, Schultz PG, Hayallah AM, Thomas KR, Famulok M, Zhang K, Ginsberg MH, Li DY (2009) Slit2-Robo4 signaling promotes vascular stability by blocking Arf6 activity. Nature Cell Biology, In Press
2. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London MR, Ling J, Mayo AH, Drakos SG, Marchuk DA, Davis GE, Li DY (2009) The Cerebral Cavernous Malformation signaling pathway promotes vascular integrity via Rho GTPase. Nature Medicine Feb;15(2):177-84
3. Jones C, London N, Park K, Chen H, Stockton R, Nishiya N Ginsberg M, Zhang K, Li DY (2008) Robo4 signaling inhibits pathologic retinal vascular leak and neovascularization. In Review
4. Navankasattusas S, Whitehead K, Suli A, Sorensen LK, Lim A, Zhao J, Thomas KR, Chien C, Li DY (2008) The netrin receptor, Unc5b, promote angiogenesis in specific vascular beds. Development, In Press
5. Wagenseil JE, Knutsen RH, Li DY, Mecham RP (2007) Elastin insufficient mice show normal cardiovascular remodeling in 2K1C hypertension, despite higher baseline pressure and unique cardiovascular architecture. Am J Physiol Heart Circ Physiol. Epub
6. Wachi H, Sato F, Hakazawa J, Nonaka R, Szabo Z, Urban Z, Tasubaga T, Maeda I, Okamoto K, Starcher B, Li DY, Mecham R, Seyama Y (2006) Domains 16 and 17 of tropoelastin in elastic fiber formation Biochemistry 402(1):63-70
7. Wilson B, Park KW, Li M, Suli A, Koch GA, Sorensen L, Urness L, Chien CB, Losordo D, Li DY (2005) Netrins promote developmental and theraeutic angiogenesis. Science 313:640-4
8. Wagenseil JE, Neurrukar NL, Knutsen RH, Okamoto RJ, Li DY, Mecham RP (2005) Effects of elastin haploinsufficiency on the mechanical behavior of mouse arteries. American Journal of Physiology, In Press
9. Park KW, Urness LD, Senchuk MM, Colvin CJ, Chien CB, Li DY (2005) Identification of new netrin family members in zebrafish: Developmental expression of netrin2 and netrin4 . Developmental Dynamics, In Press
10. Bedell V, Yeo SY, Park KW, Chung J, Seth P, Shivalingappa V, Zhao J, Obara T, Sukhatme V, Drummond I, Chitnis A, Li DY, Ramchandran R (2005) Robo4 is essential for angiogenesis in vivo. PNAS, In Press
11. Spencer JA, Hacker SL, Davis EC, Mecham RP, Knutsen RH, Li DY, Gerard RD, Richardson RA, Olson EN, Yanisgisawa H (2005) A novel role of fibulin-5 as a negative regulator of vascular remodeling. PNAS 102(8):2946-51
12. Park KY, Crouse D, Lee M, Karnik S, Sorenson L, Kuo C, Li DY (2004) The axonal attractant, netrin-1, is a potent angiogenic factor. PNAS 101:16210-5
13. Urness L, Li DY (2004) Wiring the vascular circuitry: from growth factors to guidance cues. Curr Top Dev Biol. 62:87-126
14. Whitehead K, Plummer N, Adams J, Marchuk D, Li DY (2004) Disrupted arterial morphogenesis in mice lacking Ccm1 ; implications for the etiology of cavernous malformation. Development 131(6):1437-48
15. Faury G, Pezet M, Boyle WA, Knutsen R, Hexamer SP, McLean SE, Minkes RK, Blumer KJ, Kelly DP, Starcher B, Li DY, Mecham RP (2003) Developmental adaptation of the mouse cardiovascular system to elastin haploisufficiency. JCI 112(9):1419-28
16. Karnik SK, Wythe JD, Sorenson LK, Li DY (2003) Elastin hexapeptide activates myofibrillinogenesis in vascular smooth muscle cells. Matrix Biology 22(5):409-425
17. Brooke BS, Bayes-Genis A, Li DY (2003) Elastin in vascular diseases. Trends in Cardiovascular Medicine 13:176-81
