Dean Y. Li

Professor of Medicine and
Adjunct Professor of Oncological Sciences and of Human GeneticsDean Li

Chief Scientific Officer for U of U Health Sciences
Associate VP for Research, University of Utah Health Sciences
Director, Molecular Medicine Program
Interim Co-Chair, Department of Physiology
Vice Dean for Research, School of Medicine

B.A. University of Chicago

M.D. Washington University

Ph.D. Washington University

Research

References

dean.li@u2m2.utah.edu

Dean Li's Lab Page

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 131:1437-48; Nature Medicine 15:177-84; Journal of Clinical Investigations 121:1871-81). 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 (Development 135:659-67; Science 313:640-4). Slits enhance vascular stability and inhibit pathologic angiogenesis and endothelial hyperpermeability via an endothelial-specific Robo receptors (Nature Medicine 14:448-53; Nature Cell Biology 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 492:252-255; J Immunol. 192(12):6045-52).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.  Our laboratory has used these mechanistic insights and applied them to the study of cancer biology (Science Signaling 6(265):ra14). 

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 126:230-41; Journal American College Cardiology 56:382-91). We seek to uncover the mechanisms responsible for unprecedented cardiac recovery/regeneration in this unique patient population.

Li Figure 2 Li Figure 1 Cover 3

 Selected References

  1. Davis CT, Zhu W, Gibson CC, Bowman-Kirgin J, Sorensen L, Ling J, Sun H, Navankasattusas S and Li DY. (2014) ARF6 inhibition stabilizes the vasculature and enhances survival during endotoxic shock. J Immunol. 192(12):6045-52
  2. Grossman AH, Yoo JH, Clancy J, Sorensen LK, Sedgewick A, Tong ZZ, Ostanin K, Rogers A, Grossman KF, Tripp SR, Thomas KR, D’Souza-Schorey C, Odelberg SJ and Li DY (2013) The Small GTPase ARF6 Regulates ß-catenin Transactivation during WNT5A-Mediated Melanoma Invasion and Metastasis. Science Signaling 6(265):ra14
  3. Zhu W, London NR, Gibson CC, Davis CT, Tong Z, Sorensen LK, Shi DS, Guo J, Smith MC, Grossmann AH, Thomas KR and Li DY (2012) Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature 492(7428):252-255
  4. Sawada J, Urakami T, Li F, Urakami A, Zhu W, Fukuda M, Li DY, Ruoslahti E and Komatsu M (2012) Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels. Cancer Cell 22(2):235-249
  5. Drakos SG, Kfoury AG, Stehlik J, Selzman CH, Reid BB, Terrovitis JV, Nanas JN and Li DY (2012) Bridge to recovery: understanding the disconnect between clinical and biological outcomes. Circulation 126(2):230-41
  6. 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 and Li DY (2011) Mutations in two distinct genetic pathways result in cerebral cavernous malformations in mice. Journal of Clinical Investigations 121(5):1871-1881
  7. Lim AH, Suli A, Yaniv K, Weinstein B, Li DY* and Chien CB (2011) Motoneurons are essential for vascular pathfinding. Development 138(17):3847-3857 *Corresponding author
  8. Larrieu-Lahargue F, Welm AL, Thomas KR and Li DY (2011) Netrin-4 Activates Endothelial Integrin {alpha}6{beta}1. Circulation Research 109(7):770-774
  9. 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 and 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 56(5):382-391
  10. 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 and Li DY (2010) Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza. Science Translational Medicine 2(23):ra19
  11. 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 and Li DY (2009) Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature Cell Biology 11(11):1325-1331
  12. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London MR, Ling J, Mayo AH, Drakos SG, Marchuk DA, Davis GE and Li, DY (2009) The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nature Medicine 15(2):177-184
  13. 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):448-453
  14. 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):659-667
  15. 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):640-644
  16. 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):1437-1448
  17. 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
  18. 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(1):251-267
  19. Urness LD, Sorensen LK and Li DY (2000) Arteriovenous malformations in mice lacking activin-like kinase receptor 1. Nature Genetics 26(3):328-331
  20. 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(5419):1534-1537
  21. 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. Journal of Clinical Investigation 102(10):1783-1787
  22. Li DY, Brooke B, Davis EC, Sorensen LK, Boak BB, Eichwald E, Mecham RP and Keating MT (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393(6682):276-280

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Last Updated: 7/17/14