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

  • July 12, 2024 - June 12, 2025 - Induction, fate and function of inflammatory fibroblasts , Principal Investigator . Sponsor: NIH, Sponsor Award ID: RO1HL171159
  • 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
  • August 1, 2018 - July 31, 2019 - 20th Biennial International Conference on Lung and Airway Fibrosis (ICLAF) , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13HL140841
  • September 1, 2014 - June 30, 2019 - Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1. , Principal Investigator . Sponsor: NIH, Sponsor Award ID: UH3HL123423
  • August 9, 2012 - July 31, 2018 - Targeting epithelial cells to treat pulmonary fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P01HL108794
  • September 1, 2014 - July 14, 2016 - Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1. , Principal Investigator . Sponsor: NIH, Sponsor Award ID: UH2HL123423
  • December 3, 2010 - November 30, 2015 - Integrin-mediated Regulation of Airway Smooth Muscle , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL102292
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • April 1, 1995 - March 31, 2015 - In Vivo Function of Pulmonary Integrins , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37HL053949
  • April 1, 2006 - March 31, 2011 - Regulation of Pulmonary Vascular Permeability by Integrin AlphaVBeta5 , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL083950
  • September 1, 1988 - February 28, 2010 - Novel Leukocyte Integrins , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI024674
  • February 1, 2000 - November 30, 2009 - Integrin-Mediated Development of the Thoracic Duct , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL064353
  • April 1, 1995 - March 31, 2009 - In Vivo Function of Pulmonary Integrins , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL053949
  • September 30, 2000 - July 31, 2008 - The NHLBI-Bay Area Functional Genomics Consortium , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01HL066600
  • January 17, 2003 - December 31, 2007 - Conference on Fibronectin, Integrins &Related Molecules , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13CA097981
  • September 30, 1996 - August 31, 2006 - Interactions of Lymphocytes, Cytokines and Airway Cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P50HL056385
  • June 1, 1994 - June 30, 2005 - SCIENTIFIC REVIEW AND EVALUATION GRANT , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: U09HL053927
  • September 30, 1996 - August 31, 2001 - MECHANISMS OF PERSISTENT AIRWAY INFLAMMATION IN ASTHMA , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P01HL056385
  • January 23, 1992 - May 31, 2000 - FUNCTION OF A NOVEL AIRWAY EPITHELIAL ADHESION RECEPTOR , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL047412
  • September 20, 1985 - August 31, 1998 - AIRWAY EPITHELIAL RECEPTORS FOR EXTRACELLULAR MATRIX , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL033259

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. Tsukui T, Sheppard D. Stromal heterogeneity in the adult lung delineated by single-cell genomics. Am J Physiol Cell Physiol. 2025 May 12.  View on PubMed
  2. Hou D, Wang S, Castro BA, Katz JL, Dapash M, Arrieta VA, Vazquez-Cervantes GI, Wan H, Billingham LK, Du R, Murphy AR, Lopez-Rosas A, Han Y, Patel RV, Chia TY, Dmello CC, Zhang P, Sheppard D, Sonabend AM, Miska JM, Lesniak MS, Heiland DH, Lee-Chang C. Dual αVβ8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Glioma Immunity. Neuro Oncol. 2025 Apr 22.  View on PubMed
  3. Neumann A, Sammallahti S, Cosin-Tomas M, Reese SE, Suderman M, Alemany S, Almqvist C, Andrusaityte S, Arshad SH, Bakermans-Kranenburg MJ, Beilin L, Breton C, Bustamante M, Czamara D, Dabelea D, Eng C, Eskenazi B, Fuemmeler BF, Gilliland FD, Grazuleviciene R, Håberg SE, Herberth G, Holland N, Hough A, Hu D, Huen K, Hüls A, Jarvelin MR, Jin J, Julvez J, Koletzko BV, Koppelman GH, Kull I, Lu X, Maitre L, Mason D, Melén E, Merid SK, Molloy PL, Mori TA, Mulder RH, Page CM, Richmond RC, Röder S, Ross JP, Schellhas L, Sebert S, Sheppard D, Snieder H, Starling AP, Stein DJ, Tindula G, van IJzendoorn MH, Vonk J, Walton E, Witonsky J, Xu CJ, Yang IV, Yousefi PD, Zar HJ, Zenclussen AC, Zhang H, Tiemeier H, London SJ, Felix JF, Cecil C. Epigenetic timing effects on child developmental outcomes: a longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium. Genome Med. 2025 Apr 14; 17(1):39.  View on PubMed
  4. McKinsey GL, Santander N, Zhang X, Kleemann KL, Tran L, Katewa A, Conant K, Barraza M, Waddell K, Lizama CO, La Russa M, Koo JH, Lee H, Mukherjee D, Paidassi H, Anton ES, Atabai K, Sheppard D, Butovsky O, Arnold TD. Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity. Nat Commun. 2025 Mar 22; 16(1):2840.  View on PubMed
  5. Wang K, Farrell A, Zhou E, Qin H, Zeng Z, Zhou K, Cunha E Rocha K, Zhang D, Wang G, Atakilit A, Sheppard D, Lu LF, Jin C, Ying W. ATF4 drives regulatory T cell functional specification in homeostasis and obesity. Sci Immunol. 2025 Mar 14; 10(105):eadp7193.  View on PubMed
  6. Moore CM, Secor EA, Fairbanks-Mahnke A, Everman JL, Elhawary JR, Witonsky JI, Pruesse E, Chang CH, Contreras MG, Eng C, Canales K, Rosado T, Hu D, Huntsman S, Jackson ND, Li Y, Lopez N, Valentin AM, Medina V, Montanez-Lopez CA, Morin A, Nieves NA, Oh SS, Otero RA, Colon R, Rodriguez L, Sajuthi SP, Salazar S, Serrano G, Morales EV, Vazquez G, Morales NV, Williams BJM, Zhang P, Sheppard D, Rodriguez Santana JR, Seibold MA. Independent and interactive effects of viral species on risk for lower respiratory tract illnesses in early life. medRxiv. 2025 Feb 26.  View on PubMed
  7. Fang Y, Chung SSW, Xu L, Xue C, Liu X, Jiang D, Li R, Korogi Y, Yuan K, Saqi A, Hibshoosh H, Huang Y, Lin CS, Tsukui T, Sheppard D, Sun X, Que J. RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition. Nature. 2025 Feb 05.  View on PubMed
  8. Kumar R, Nolan K, Kassa B, Chanana N, Palmo T, Sharma K, Singh K, Mickael C, Fonseca Balladares D, Nilsson J, Prabhakar A, Mishra A, Lee MH, Sanders L, Kumar S, Molofsky AB, Stenmark KR, Sheppard D, Tuder RM, Gupta MD, Thinlas T, Pasha Q, Graham BB. Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension. J Clin Invest. 2025 Jan 30; 135(6).  View on PubMed
  9. 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
  10. 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
  11. 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
  12. 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
  13. Tsukui T, Wolters PJ, Sheppard D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature. 2024 Jul; 631(8021):627-634.  View on PubMed
  14. 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
  15. 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
  16. Ewing-Crystal NA, Mroz NM, Chang AA, Merrill ED, Caryotakis SE, Teo L, Larpthaveesarp A, Tsukui T, Katewa A, Pennington R, McKinsey GL, Nelson S, Ciesielska A, Dahlgren MW, Paidassi H, Jain S, Aghi MK, Bourne JA, Paz JT, Gonzalez FF, Sheppard D, Molofsky AV, Arnold TD, Molofsky AB. Dynamic fibroblast-immune interactions shape wound healing after brain injury. bioRxiv. 2024 Mar 15.  View on PubMed
  17. 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
  18. 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 03; 9(93):eadj7363.  View on PubMed
  19. 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
  20. 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

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