Research Summary

Dean Sheppard is a Professor of Medicine. His research focuses on the in vivo functions of integrins and the molecular mechanisms underlying pulmonary (and other organ) fibrosis. 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 the epithelial-restricted integrin, avß6, and the widely expressed integrins, a5ß1, a9ß1, 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. His lab identified the unique roles that 3 integrins, avß1, avß6 and avß8 play in activation of the growth factor, latent transforming growth factor beta (TGFß) and has identified critical roles for this process in acute lung injury, pulmonary fibrosis, post-natal brain development and immunosuppression in the setting of cancer. The lab has partnered with academic colleagues, biotech and pharmaceutical companies to develop novel antibody and small molecule inhibitors of these integrins that are in various stages of pre-clinical and clinical development. Current work is also using single cell RNA sequencing to understand the heterogeneity of cells that contribute to tissue fibrosis and cancer, and exploring the potential of engineering circulating cells for local delivery of novel therapeutics to fibrotic organs and tumors.

Research Funding

  • April 1, 2020 - March 31, 2024 - Fibroblast heterogeneity in pulmonary fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL142568
  • April 1, 2008 - March 31, 2023 - Understanding Asthma Endotypes , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: U19AI077439
  • January 15, 2019 - December 31, 2022 - Interventional Targeting of the IRE1alpha-TGFbeta signaling loop in pulmonary fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL145037
  • July 1, 1976 - June 30, 2022 - Multidisciplinary Training Program in Lung Disease , Principal Investigator . Sponsor: NIH, Sponsor Award ID: T32HL007185

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

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. Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry JL, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJL, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. Nat Immunol. 2023 Sep 25.  View on PubMed
  2. Massagué J, Sheppard D. TGF-β signaling in health and disease. Cell. 2023 09 14; 186(19):4007-4037.  View on PubMed
  3. Zhang J, Tsukui T, Wu X, Brito A, Trumble JM, Caraballo JC, Allen GM, Zavala-Solorio J, Zhang C, Paw J, Lim WA, Geng J, Kutskova Y, Freund A, Kolumam G, Sheppard D, Cohen RL. An immune-based tool platform for in vivo cell clearance. Life Sci Alliance. 2023 08; 6(8).  View on PubMed
  4. Sikkema L, Ramírez-Suástegui C, Strobl DC, Gillett TE, Zappia L, Madissoon E, Markov NS, Zaragosi LE, Ji Y, Ansari M, Arguel MJ, Apperloo L, Banchero M, Bécavin C, Berg M, Chichelnitskiy E, Chung MI, Collin A, Gay ACA, Gote-Schniering J, Hooshiar Kashani B, Inecik K, Jain M, Kapellos TS, Kole TM, Leroy S, Mayr CH, Oliver AJ, von Papen M, Peter L, Taylor CJ, Walzthoeni T, Xu C, Bui LT, De Donno C, Dony L, Faiz A, Guo M, Gutierrez AJ, Heumos L, Huang N, Ibarra IL, Jackson ND, Kadur Lakshminarasimha Murthy P, Lotfollahi M, Tabib T, Talavera-López C, Travaglini KJ, Wilbrey-Clark A, Worlock KB, Yoshida M, Lung Biological Network Consortium, van den Berge M, Bossé Y, Desai TJ, Eickelberg O, Kaminski N, Krasnow MA, Lafyatis R, Nikolic MZ, Powell JE, Rajagopal J, Rojas M, Rozenblatt-Rosen O, Seibold MA, Sheppard D, Shepherd DP, Sin DD, Timens W, Tsankov AM, Whitsett J, Xu Y, Banovich NE, Barbry P, Duong TE, Falk CS, Meyer KB, Kropski JA, Pe'er D, Schiller HB, Tata PR, Schultze JL, Teichmann SA, Misharin AV, Nawijn MC, Luecken MD, Theis FJ. An integrated cell atlas of the lung in health and disease. Nat Med. 2023 Jun; 29(6):1563-1577.  View on PubMed
  5. Livanos AE, Dunn A, Fischer J, Ungaro RC, Turpin W, Lee SH, Rui S, Del Valle DM, Jougon JJ, Martinez-Delgado G, Riddle MS, Murray JA, Laird RM, Torres J, Agrawal M, Magee JS, Dervieux T, Gnjatic S, Sheppard D, Sands BE, Porter CK, Croitoru K, Petralia F, CCC-GEM Project Research Consortium, OSCCAR Consortium, Colombel JF, Mehandru S. Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis. Gastroenterology. 2023 04; 164(4):619-629.  View on PubMed
  6. Monieri M, Rainone P, Sacchi A, Gori A, Gasparri AM, Coliva A, Citro A, Ferrara B, Policardi M, Valtorta S, Pocaterra A, Alfano M, Sheppard D, Piemonti L, Moresco RM, Corti A, Curnis F. A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins. Int J Biol Sci. 2023; 19(1):156-166.  View on PubMed
  7. Reyes NS, Krasilnikov M, Allen NC, Lee JY, Hyams B, Zhou M, Ravishankar S, Cassandras M, Wang C, Khan I, Matatia P, Johmura Y, Molofsky A, Matthay M, Nakanishi M, Sheppard D, Campisi J, Peng T. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science. 2022 10 14; 378(6616):192-201.  View on PubMed
  8. Bhattacharyya A, Torre P, Yadav P, Boostanpour K, Chen TY, Tsukui T, Sheppard D, Muramatsu R, Seed RI, Nishimura SL, Jung JB, Tang XZ, Allen CDC, Bhattacharya M. Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury. Front Immunol. 2022; 13:880887.  View on PubMed
  9. Bapat SP, Whitty C, Mowery CT, Liang Y, Yoo A, Jiang Z, Peters MC, Zhang LJ, Vogel I, Zhou C, Nguyen VQ, Li Z, Chang C, Zhu WS, Hastie AT, He H, Ren X, Qiu W, Gayer SG, Liu C, Choi EJ, Fassett M, Cohen JN, Sturgill JL, Crotty Alexander LE, Suh JM, Liddle C, Atkins AR, Yu RT, Downes M, Liu S, Nikolajczyk BS, Lee IK, Guttman-Yassky E, Ansel KM, Woodruff PG, Fahy JV, Sheppard D, Gallo RL, Ye CJ, Evans RM, Zheng Y, Marson A. Obesity alters pathology and treatment response in inflammatory disease. Nature. 2022 04; 604(7905):337-342.  View on PubMed
  10. Auyeung VC, Downey MS, Thamsen M, Wenger TA, Backes BJ, Sheppard D, Papa FR. IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2022 04 01; 322(4):L564-L580.  View on PubMed
  11. Shihan MH, Novo SG, Wang Y, Sheppard D, Atakilit A, Arnold TD, Rossi NM, Faranda AP, Duncan MK. αVβ8 integrin targeting to prevent posterior capsular opacification. JCI Insight. 2021 11 08; 6(21).  View on PubMed
  12. Lainé A, Labiad O, Hernandez-Vargas H, This S, Sanlaville A, Léon S, Dalle S, Sheppard D, Travis MA, Paidassi H, Marie JC. Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation. Nat Commun. 2021 10 28; 12(1):6228.  View on PubMed
  13. Dodagatta-Marri E, Ma HY, Liang B, Li J, Meyer DS, Chen SY, Sun KH, Ren X, Zivak B, Rosenblum MD, Headley MB, Pinzas L, Reed NI, Del Cid JS, Hann BC, Yang S, Giddabasappa A, Noorbehesht K, Yang B, Dal Porto J, Tsukui T, Niessen K, Atakilit A, Akhurst RJ, Sheppard D. Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Rep. 2021 07 06; 36(1):109309.  View on PubMed
  14. Liu S, Ngo U, Tang XZ, Ren X, Qiu W, Huang X, DeGrado W, Allen CD, Jo H, Sheppard D, Sundaram AB. Integrin α2β1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models. J Clin Invest. 2021 06 15; 131(12).  View on PubMed
  15. Auyeung VC, Sheppard D. Stuck in a Moment: Does Abnormal Persistence of Epithelial Progenitors Drive Pulmonary Fibrosis? Am J Respir Crit Care Med. 2021 03 15; 203(6):667-669.  View on PubMed
  16. Nishimichi N, Tsujino K, Kanno K, Sentani K, Kobayashi T, Chayama K, Sheppard D, Yokosaki Y. Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis. J Pathol. 2021 04; 253(4):366-373.  View on PubMed
  17. Wong JC, Perez-Mancera PA, Huang TQ, Kim J, Grego-Bessa J, Del Pilar Alzamora M, Kogan SC, Sharir A, Keefe SH, Morales CE, Schanze D, Castel P, Hirose K, Huang GN, Zenker M, Sheppard D, Klein OD, Tuveson DA, Braun BS, Shannon K. KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice. JCI Insight. 2020 11 05; 5(21).  View on PubMed
  18. Cassandras M, Wang C, Kathiriya J, Tsukui T, Matatia P, Matthay M, Wolters P, Molofsky A, Sheppard D, Chapman H, Peng T. Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung. Nat Cell Biol. 2020 11; 22(11):1295-1306.  View on PubMed
  19. Sundaram A, Chen C, Isik Reed N, Liu S, Ki Yeon S, McIntosh J, Tang YZ, Yang H, Adler M, Beresis R, Seiple IB, Sheppard D, DeGrado WF, Jo H. Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness. Bioorg Med Chem Lett. 2020 11 15; 30(22):127578.  View on PubMed
  20. Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, Hu JK, Schaub JR, Ho SS, Rao V, Marlow MM, Turner SM, Sedki M, Pantano L, Ghoshal S, Ferreira DDS, Ma HY, Duwaerts CC, Espanol-Suner R, Wei L, Newcomb B, Mileva I, Canals D, Hannun YA, Chung RT, Mattis AN, Fuchs BC, Tager AM, Yimlamai D, Weaver VM, Mullen AC, Sheppard D, Chen JY. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci Transl Med. 2020 08 19; 12(557).  View on PubMed

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