Research Summary

Dean Sheppard is a Professor of Medicine. His research focuses on the molecular mechanisms underlying pulmonary (and other organ) fibrosis, acute lung injury and immune responses to solid tumors. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work began 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.

Current work is using single cell RNA sequencing to understand the heterogeneity of cells that contribute to tissue fibrosis and using these results to generate novel murine lines to establish the lineage, fate and functional importance of each of the new cell states identified. The lab is also collaborating with Wendell Lim to use these data to engineer cells that delivery genetically encoded therapeutics at sites of fibrosis and acute lung injury and to improve cell-based therapies for solid 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. Khan IS, Molina C, Ren X, Auyeung VC, Cohen M, Tsukui T, Atakilit A, Sheppard D. Impaired myofibroblast proliferation is a central feature of pathologic post-natal alveolar simplification. Elife. 2024 Dec 11; 13.  View on PubMed
  2. Khan IS, Molina C, Ren X, Auyeung VC, Cohen M, Tsukui T, Atakilit A, Sheppard D. Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification. bioRxiv. 2024 Sep 16.  View on PubMed
  3. Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, Sheppard D, Sundaram AB. IL-13 and IL-17A activate β1 integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle. Proc Natl Acad Sci U S A. 2024 Aug 20; 121(34):e2401251121.  View on PubMed
  4. Yadav P, Ortega JG, Tamaki W, Chien C, Chang KC, Biswas N, Pan S, Nilsson J, Yin X, Bhattacharyya A, Boostanpour K, Jujaray T, Wang J, Tsukui T, Sheppard D, Li B, Maishan M, Taenaka H, Matthay MA, Muramatsu R, Maliskova L, Ghosh A, Eckalbar WL, Molofsky AB, Wolters PJ, Tamaki SJ, Bivona T, Abate AR, Wagner A, Tharp KM, Bhattacharya M. Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading. bioRxiv. 2024 Jul 31.  View on PubMed
  5. Tsukui T, Wolters PJ, Sheppard D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature. 2024 Jul; 631(8021):627-634.  View on PubMed
  6. Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, Sheppard D, Sundaram AB. IL-13 and IL-17A Activate β1 Integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to Enhance Force Transmission in Airway Smooth Muscle. bioRxiv. 2024 May 01.  View on PubMed
  7. Witonsky JI, Elhawary JR, Eng C, Oh SS, Salazar S, Contreras MG, Medina V, Secor EA, Zhang P, Everman JL, Fairbanks-Mahnke A, Pruesse E, Sajuthi SP, Chang CH, Guerrero TR, Fuentes KC, Lopez N, Montanez-Lopez CA, Otero RA, Rivera RC, Rodriguez L, Vazquez G, Hu D, Huntsman S, Jackson ND, Li Y, Morin A, Nieves NA, Rios C, Serrano G, Williams BJM, Ziv E, Moore CM, Sheppard D, Burchard EG, Seibold MA, Rodriguez Santana JR. The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children. medRxiv. 2024 Apr 16.  View on PubMed
  8. Lee JY, Reyes NS, Ravishankar S, Zhou M, Krasilnikov M, Ringler C, Pohan G, Wilson C, Ang KK, Wolters PJ, Tsukui T, Sheppard D, Arkin MR, Peng T. An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis. J Clin Invest. 2024 Mar 07; 134(9).  View on PubMed
  9. De Giovanni M, Vykunta VS, Biram A, Chen KY, Taglinao H, An J, Sheppard D, Paidassi H, Cyster JG. Mast cells help organize the Peyer's patch niche for induction of IgA responses. Sci Immunol. 2024 Mar; 9(93):eadj7363.  View on PubMed
  10. Vukmirovic M, Benam KH, Rose JJ, Turner S, Magin CM, Lagares D, Cohen AH, Kaminski N, Hirota JA, Maher TM, Konigshoff M, Mallampalli RK, Sheppard D, Tarran R, Gomer RH, Kenyon NJ, Morris D, Hobbie S, Raju SV, Petrache I, Watkins T, Kumar R, Lam WA, Sherer T, Hecker L. Challenges and Opportunities for Commercializing Technologies in the Pulmonary Arena: An Official American Thoracic Society Report. Ann Am Thorac Soc. 2024 Jan; 21(1):1-11.  View on PubMed
  11. 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 Nov; 24(11):1839-1853.  View on PubMed
  12. McKinsey GL, Santander N, Zhang X, Kleemann K, Tran L, Katewa A, Conant K, Barraza M, Waddell K, Lizama C, La Russa M, Koo HJ, Lee H, Mukherjee D, Paidassi H, Anton ES, Atabai K, Sheppard D, Butovsky O, Arnold TD. Radial glia promote microglial development through integrin αVβ8 -TGFβ1 signaling. bioRxiv. 2023 Sep 21.  View on PubMed
  13. Massagué J, Sheppard D. TGF-β signaling in health and disease. Cell. 2023 09 14; 186(19):4007-4037.  View on PubMed
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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

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