Dean Y. Li

Distinguished Professor of Medicine and of
Oncological Sciences and of Human Genetics

Additional Titles

Vice Dean for Research, University of Utah School of Medicine

Chief Scientific Officer, University Health Care

Dean Li

B.A. University of Chicago

M.D. Washington University

Ph.D. Washington University

Research

References

dean.li@u2m2.utah.edu

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 (Journal Clinical Investigations 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: Nature Medicine 15(2):177-84: Journal of Clinical Investigations 121(5):1871-81). These discoveries have allowed us to discover a new signaling cascade that regulates cell shape and junctions.

As a 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 Robo receptors (Nature Medicine 14(4):448-53: Nature Cell Biology 11(11):1325-31). 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 known 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 to find small molecule inflammatory modulators that will be effective in regulating vascular regeneration and stability of human diseases (Nature In Press).These vascular guidance studies have fueled my hypothesis that inflammatory signals trigger cell dissociation by a common regulatory mechanism that is independent of classic inflammatory signaling pathways uncoupling the direct disruptive effects of inflammatory cytokines from their effects on transcriptional immunomodulatory pathways.

My clinical cardiology practice and interest in inflammation have led me to study mechanisms of human cardiovascular recovery and regeneration. In this effort we have enlisted all heart failure/left ventricle assist device patients in Utah and the surrounding area (Circulation 126(2):230-41: Journal American College Cardiology 56(5):382-91). We seek to uncover the mechanisms responsible for unprecedented cardiac recovery/regeneration in this unique patient population.

Li Figure 2 Li Figure 1

 Selected References

  1. Li DY, Brooke B, Davis EC, Sorensen LK, Boak BB, Eichwald E, Mecham RP Keating MT (1998) Elastin is an essential determinant of arterial morphogenesis: Nature 393:276-280
  2. Li DY, Faury G, Taylor DG, Davis EC, Boyle WA, Mecham RP, Stenzel P, Boak B and Keating MT (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102: 1783-1787
  3. Li, DY, Sorensen, LK, Brooke B, Urness LD, Davis EC, Taylor D, Boak B and Wendel D (1999) Defective angiogenesis in mice lacking endoglin. Science 284: 1534-1537
  4. Urness LD, Sorensen LK, and Li DY (2000) Arteriovenous malformations in mice lacking activin-like kinase receptor 1. Nature Genetics 26: 328-331
  5. Park KW, Morrison CM, Sorenson LK, Chien CB, Wu JY and Li DY (2003) Robo4 is a vascular-specific receptor that inhibits endothelial migration. Developmental Biology 261:251-267
  6. Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS, Keating MT and Li DY (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130(2):411-420
  7. Whitehead K, Plummer N, Adams J, Marchuk D, and Li DY (2004) Disrupted arterial morphogenesis in mice lacking Ccm1; implications for the etiology of cavernous malformation. Development 131(6):1437-48
  8. Wilson B, Park KW, Li M, Suli A, Koch GA, Sorensen L, Urness L, Chien CB, Losordo D, and Li DY (2006) Netrins promote developmental and therapeutic angiogenesis. Science 313(5787):640-4
  9. Navankasattusas S, Whitehead K, Suli A, Sorensen LK, Lim A, Zhao J, Thomas KR, Chien C, and Li DY (2008) The netrin receptor, Unc5b, promote angiogenesis in specific vascular beds. Development 135(4):659-67
  10. Jones C, London N, Park K, Chen H, Stockton R, Nishiya N Ginsberg M, Zhang K, and Li DY (2008) Robo4 stabilizes the vasculature by inhibiting angiogenesis and endothelial hyperpermeability. Nature Medicine 14(4):448-53
  11. 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 GTPases. Nature Medicine Feb;15(2):177-84
  12. 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 signalling promotes vascular stability by blocking Arf6 activity. Nature Cell Biology 11(11):1325-31
  13. London NR, Zhu W, Bozza FA, Smith MCP, Greif DM, Sorenson LK, Chen L, Kaminoh Y, Chan AC, Passi SF, Day CW, Barnard DL, Zimmerman GA, Krasnow MA, Li DY (2010) Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza. Science Translational Medicine Mar 17; 2(23), ra19
  14. Drakos SG, Kfoury AG, Hammond EH, Reid BB, Revelo MP, Rasmusson BY, Whitehead KJ, Salama ME, Selzman CH, Stehlik J, Clayson SE, Bristow MR, Renlund DG, Li DY (2010) Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart. Journal of the American College of Cardiology Jul 27; 56(5):382-91
  15. Larrieu-Lahargue F, Welm AL, Thomas KR, Li DY (2011) Netrin-4 Activates Endothelial Integrin {alpha}6{beta}1. Circulation Research Sep 16; 109(7):770-4 (Epub 2011 Jul 28)
  16. Lim AH, Suli A, Yaniv K, Weinstein B, Li DY*, Chien CB (2011) Motoneurons are essential for vascular pathfinding. Development Sep; 138(17):3847-57 *Corresponding author
  17. Chan AC, Drakos SG, Ruiz OE, Smith AC, Gibson CC, Ling J, Passi SF, Stratman AN, Sacharidou A, Revelo MP, Grossmann AH, Diakos NA, Davis GE, Metzstein MM, Whitehead KJ, Li DY (2011) Mutations in two distinct genetic pathways result in cerebral cavernous malformations in mice. Journal of Clinical Investigations May 2; 121(5):1871-81
  18. Sawada J, Urakami T, Li F, Urakami A, Zhu W, Fukuda M, Li DY, Ruoslahti E, Komatsu M (2012) Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels. Cancer Cell. 22(2):235-49
  19. Zhu W, London NR, Gibson CC, Davis CT, Tong ZZ, Sorensen LK, Shi DS, Guo J, Smith MCP, Grossman AH, Thomas KR, Li DY (2012) Interleukin receptor activates a MyD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature In Press

 

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Last Updated: 3/14/13