Dean Sheppard, MD

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Dean Sheppard, MD

Professor, Department of Medicine, UCSF

dean.sheppard@ucsf.edu

Phone: (415) 514-4269 (voice)
Box 2922, UCSF
San Francisco, CA 94143-2922

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Research Summary

Dean Sheppard received an AB (Social Studies) from Harvard College in 1972, and an MD from SUNY at Stony Brook in 1975. He trained in Internal Medicine at the University of Washington in Seattle and in Pulmonary Medicine at UCSF. He has been on the faculty of UCSF since 1980 and was appointed the founding director of the Lung Biology Research Center in 1986. He has been the Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep since 2009. Dr. Sheppard is Professor of Medicine and a member of the Cell Biology, Biomedical Sciences, Immunology and Pharmaceutical Sciences and Pharmacogenomics graduate programs.

Research Interests

Dr. Sheppard’s research focuses on the molecular mechanisms underlying pulmonary (and other organ) fibrosis, asthma and acute lung injury. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common lung diseases. Utilizing mice with global or conditional knockouts of four integrins, the epithelial-restricted integrin, avß6, and the widely expressed integrins a9ß1, avß1, avß5 and avß8, the lab has identified important roles for these integrins in models of each common lung disease and key steps upstream and downstream of the integrins that provide potential therapeutic targets.

avß6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFß), that depend on distinct sequences in the ß6 cytoplasmic domain. We have shown that the latter function plays a central role in pulmonary and renal fibrosis, acute lung injury, protection from pulmonary emphysema, tumor invasion and in the airway hyperresponsiveness that follows chronic allergen challenge. Currently we are identifying pathways that regulate each of these responses. A humanized monoclonal antibody generated by immunizing our knockout mice is currently in clinical trials for treatment of pulmonary and renal fibrosis. We have also found that mice lacking all av integrins on myofibroblasts are protected from pulmonary, hepatic and renal fibrosis and are using this model to develop new approaches for treating a wide variety of fibrotic diseases.

The avß8 integrin also activates TGFß. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting avß8-mediated TGFß activation on dendritic cells negatively regulates adaptive immunity. However, these mice are dramatically protected from pathology in a number of immune-mediated disease models, including a model of allergic asthma. We are currently characterizing the mechanisms underlying these effects, the mechanisms by which this process is regulated during the induction of adaptive immune responses, and the relevance of this pathway in various models of immune-mediated disease.

The avß1 integrin is an understudied integrin that is expressed on fibroblasts and smooth muscle cells. Together with Bill DeGrado, we have generated a potent and specific small molecule inhibitor of this integrin and shown that also activates TGFß and plays a critical role in driving tissue fibrosis in several organs, including the lung, kidney and liver. We are currently working to develop even better small molecule inhibitors and reagents that will allow us to more accurately follow expression of this integrin in vivo.

a9ß1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. a9ß1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. As a9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. Mice lacking this integrin in airway smooth muscle cells develop spontaneous airway hyperresponsiveness, resembling asthma. We have used these mice and cells and tissues from their lungs to identify a completely novel pathway regulating airway smooth muscle contraction, and are currently working to develop specific inhibitors of pathway components in the hope of finding new treatments for asthma.

avß5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice are dramatically protected in multiple models of acute lung injury and septic shock. This phenotype is explained, at least in part, by a central role for this integrin in regulating reorganization of the actin cytoskeleton in activated endothelial cells. We are currently examining the mechanisms by which this integrin, and its close relative, avß3, exert opposing effects on actin organization, vascular permeability and tissue edema. We have also generated a potent blocking antibody to avß5 that we hope to develop for treatment of acute lung injury and septic shock.

Education

Harvard College, Cambridge, MA, A.B., 1972
SUNY at Stony Brook, Stony Brook, NY, M.D., 1975, Medicine
Univ of Washington, Seattle, WA, Resident, 1975-78, Internal Medicine
Univ of California, San Francisco, San Francisco, Fellow, 1978-80, Pulmonary


Professional Experience

  • 1986-present
    Director, Lung Biology Center, University of California, San Francisco
  • 1981-87
    Assistant Professor of Medicine, University of California, San Francisco
  • 1987-92
    Associate Professor of Medicine, University of California, San Francisco
  • 1992-present
    Professor of Medicine, University of California, San Francisco
  • 1997-present
    Associate Chair for Biomedical Research, Department of Medicine, UCSF
  • 2000-present
    Member, NHLBI Program Project Review Committee. 1998-2002, Chair 2000-2002
  • 2004-present
    Member, Lung Injury and Repair Study Section

Honors & Awards

  • 1992
    Elected Member, American Society for Clinical Investigation
  • 1995
    Elected Member, Association of American Physicians
  • 1995
    Clean Air Award, California Lung Association
  • 1998
    Scientific Achievement Award, American Thoracic Society
  • 2004-2014
    NIH Merit Award
  • 2013
    Top 20 Translational Scientists, Nature Biotechnology
  • 2016
    UCSF Fraculty Research Lecture in Translational Science
  • 2017
    elected to American Academy of Arts and Sciences

Selected Publications

  1. Chang Y, Lau WL, Jo H, Tsujino K, Gewin L, Reed NI, Atakilit A, Nunes AC, DeGrado WF, Sheppard D. Pharmacologic Blockade of avß1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo. J Am Soc Nephrol. 2017 Feb 20.
    View on PubMed
  2. Sundaram A, Chen C, Khalifeh-Soltani A, Atakilit A, Ren X, Qiu W, Jo H, DeGrado W, Huang X, Sheppard D. Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest. 2016 Dec 05.
    View on PubMed
  3. Tsujino K, Reed NI, Atakilit A, Ren X, Sheppard D. Transforming Growth Factor ß plays divergent roles in modulating vascular remodeling, inflammation and pulmonary fibrosis in a murine model of scleroderma. Am J Physiol Lung Cell Mol Physiol. 2016 Nov 18; ajplung.00428.2016.
    View on PubMed
  4. Reed NI, Tang YZ, McIntosh J, Wu Y, Molnar KS, Civitavecchia A, Sheppard D, DeGrado WF, Jo H. Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective avß1 Integrin Inhibitors. ACS Med Chem Lett. 2016 Oct 13; 7(10):902-907.
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  5. Meliopoulos VA, Van de Velde LA, Van de Velde NC, Karlsson EA, Neale G, Vogel P, Guy C, Sharma S, Duan S, Surman SL, Jones BG, Johnson MD, Bosio C, Jolly L, Jenkins RG, Hurwitz JL, Rosch JW, Sheppard D, Thomas PG, Murray PJ, Schultz-Cherry S. An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens. PLoS Pathog. 2016 Aug; 12(8):e1005804.
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  6. McAleer JP, Nguyen NL, Chen K, Kumar P, Ricks DM, Binnie M, Armentrout RA, Pociask DA, Hein A, Yu A, Vikram A, Bibby K, Umesaki Y, Rivera A, Sheppard D, Ouyang W, Hooper LV, Kolls JK. Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. J Immunol. 2016 Jul 1; 197(1):97-107.
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  7. Reboldi A, Arnon TI, Rodda LB, Atakilit A, Sheppard D, Cyster JG. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches. Science. 2016 May 13; 352(6287):aaf4822.
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  8. Sun KH, Chang Y, Reed NI, Sheppard D. a-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFß activation or collagen production across multiple models of organ fibrosis. Am J Physiol Lung Cell Mol Physiol. 2016 May 1; 310(9):L824-36.
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  9. Mohammed J, Beura LK, Bobr A, Astry B, Chicoine B, Kashem SW, Welty NE, Igyártó BZ, Wijeyesinghe S, Thompson EA, Matte C, Bartholin L, Kaplan A, Sheppard D, Bridges AG, Shlomchik WD, Masopust D, Kaplan DH. Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-ß. Nat Immunol. 2016 Apr; 17(4):414-21.
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  10. Tsujino K, Sheppard D. Critical Appraisal of the Utility and Limitations of Animal Models of Scleroderma. Curr Rheumatol Rep. 2016 Jan; 18(1):4.
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  11. Peng ZW, Ikenaga N, Liu SB, Sverdlov DY, Vaid KA, Dixit R, Weinreb PH, Violette S, Sheppard D, Schuppan D, Popov Y. Integrin avß6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. Hepatology. 2016 Jan; 63(1):217-32.
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  12. Plaks V, Boldajipour B, Linnemann JR, Nguyen NH, Kersten K, Wolf Y, Casbon AJ, Kong N, van den Bijgaart RJ, Sheppard D, Melton AC, Krummel MF, Werb Z. Adaptive Immune Regulation of Mammary Postnatal Organogenesis. Dev Cell. 2015 Sep 14; 34(5):493-504.
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  13. Li JT, Melton AC, Su G, Hamm DE, LaFemina M, Howard J, Fang X, Bhat S, Huynh KM, O'Kane CM, Ingram RJ, Muir RR, McAuley DF, Matthay MA, Sheppard D. Unexpected Role for Adaptive aßTh17 Cells in Acute Respiratory Distress Syndrome. J Immunol. 2015 Jul 1; 195(1):87-95.
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  14. Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, Sheppard D. The avß1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med. 2015 May 20; 7(288):288ra79.
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  15. Sheppard D. Epithelial-mesenchymal interactions in fibrosis and repair. Transforming growth factor-ß activation by epithelial cells and fibroblasts. Ann Am Thorac Soc. 2015 Mar; 12 Suppl 1:S21-3.
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  16. Xu P, Bailey-Bucktrout S, Xi Y, Xu D, Du D, Zhang Q, Xiang W, Liu J, Melton A, Sheppard D, Chapman HA, Bluestone JA, Derynck R. Innate antiviral host defense attenuates TGF-ß function through IRF3-mediated suppression of Smad signaling. Mol Cell. 2014 Dec 18; 56(6):723-37.
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  17. Arnold TD, Niaudet C, Pang MF, Siegenthaler J, Gaengel K, Jung B, Ferrero GM, Mukouyama YS, Fuxe J, Akhurst R, Betsholtz C, Sheppard D, Reichardt LF. Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking aVß8-TGFß signaling in the brain. Development. 2014 Dec; 141(23):4489-99.
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  18. Bhattacharya M, Sundaram A, Kudo M, Farmer J, Ganesan P, Khalifeh-Soltani A, Arjomandi M, Atabai K, Huang X, Sheppard D. IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction. J Clin Invest. 2014 Nov; 124(11):4895-8.
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  19. Erle DJ, Sheppard D. The cell biology of asthma. J Cell Biol. 2014 Jun 9; 205(5):621-31.
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  20. Ito K, Morimoto J, Kihara A, Matsui Y, Kurotaki D, Kanayama M, Simmons S, Ishii M, Sheppard D, Takaoka A, Uede T. Integrin a9 on lymphatic endothelial cells regulates lymphocyte egress. Proc Natl Acad Sci U S A. 2014 Feb 25; 111(8):3080-5.
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