Research Summary

Dean Sheppard is a Professor of Medicine, Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep and director of the Lung Biology Center. 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/NHLBI, Sponsor Award ID: R01HL142568
  • April 1, 2008 - March 31, 2023 - Understanding Asthma Endotypes, Co-Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: U19AI077439
  • February 1, 2019 - December 31, 2022 - Interventional Targeting of the IRE1alpha-TGFbeta signaling loop in pulmonary fibrosis, Principal Investigator. Sponsor: NIH/NHLBI, Sponsor Award ID: R01HL145037
  • July 1, 1976 - June 30, 2022 - Multidisciplinary Training Program in Lung Disease, Principal Investigator. Sponsor: NIH/NHLBI, 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. Liu S, Ngo U, Tang XZ, Ren X, Qiu W, Huang X, DeGrado W, Allen CD, Jo H, Sheppard D, Sundaram AB Integrin a2ß1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models.  View on PubMed
  2. Nishimichi N, Tsujino K, Kanno K, Sentani K, Kobayashi T, Chayama K, Sheppard D, Yokosaki Y Induced hepatic stellate cell integrin, a8ß1, enhances cellular contractility and TGFß activity in liver fibrosis.  View on PubMed
  3. Auyeung VC, Sheppard D Stuck in a Moment: Does Abnormal Persistence of Epithelial Progenitors Drive Pulmonary Fibrosis?  View on PubMed
  4. 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.  View on PubMed
  5. 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.  View on PubMed
  6. 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 a5ß1/avß1 integrin for airway hyperresponsiveness.  View on PubMed
  7. 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.  View on PubMed
  8. Santander N, Lizama CO, Meky E, McKinsey GL, Jung B, Sheppard D, Betsholtz C, Arnold TD Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.  View on PubMed
  9. Tsukui T, Sun KH, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, Henderson NC, Adams TS, Schupp JC, Poli SD, Rosas IO, Kaminski N, Matthay MA, Wolters PJ, Sheppard D Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis.  View on PubMed
  10. Zhang Z, Bai M, Barbosa GO, Chen A, Wei Y, Luo S, Wang X, Wang B, Tsukui T, Li H, Sheppard D, Kornberg TB, Ma DK Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking.  View on PubMed
  11. Del Cid JS, Reed NI, Molnar K, Liu S, Dang B, Jensen SA, DeGrado W, Handford PA, Sheppard D, Sundaram AB A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.  View on PubMed
  12. Arnold TD, Lizama CO, Cautivo KM, Santander N, Lin L, Qiu H, Huang EJ, Liu C, Mukouyama YS, Reichardt LF, Zovein AC, Sheppard D Impaired aVß8 and TGFß signaling lead to microglial dysmaturation and neuromotor dysfunction.  View on PubMed
  13. Bengs S, Becker E, Busenhart P, Spalinger MR, Raselli T, Kasper S, Lang S, Atrott K, Mamie C, Vavricka SR, von Boehmer L, Knuth A, Tuomisto A, Mäkinen MJ, Hruz P, Turina M, Rickenbacher A, Petrowsky H, Weber A, Frei P, Halama M, Jenkins G, Sheppard D, Croner RS, Christoph J, Britzen-Laurent N, Naschberger E, Schellerer V, Stürzl M, Fried M, Rogler G, Scharl M ß6 -integrin serves as a novel serum tumor marker for colorectal carcinoma.  View on PubMed
  14. Bulek K, Chen X, Parron V, Sundaram A, Herjan T, Ouyang S, Liu C, Majors A, Zepp J, Gao J, Dongre A, Bodaszewska-Lubas M, Echard A, Aronica M, Carman J, Garantziotis S, Sheppard D, Li X IL-17A Recruits Rab35 to IL-17R to Mediate PKCa-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility.  View on PubMed
  15. Thamsen M, Ghosh R, Auyeung VC, Brumwell A, Chapman HA, Backes BJ, Perara G, Maly DJ, Sheppard D, Papa FR Small molecule inhibition of IRE1a kinase/RNase has anti-fibrotic effects in the lung.  View on PubMed
  16. Greenhalgh SN, Matchett KP, Taylor RS, Huang K, Li JT, Saeteurn K, Donnelly MC, Simpson EEM, Pollack JL, Atakilit A, Simpson KJ, Maher JJ, Iredale JP, Sheppard D, Henderson NC Loss of Integrin avß8 in Murine Hepatocytes Accelerates Liver Regeneration.  View on PubMed
  17. Fong V, Hsu A, Wu E, Looney AP, Ganesan P, Ren X, Sheppard D, Wicher SA, Thompson MA, Britt RD, Prakash YS, Bhattacharya M Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice.  View on PubMed
  18. Podolsky MJ, Gupta D, Ha A, Ta R, Khalifeh-Soltani A, McKleroy W, Datta R, Sheppard D, Atabai K Cell division cycle 7 kinase is a negative regulator of cell-mediated collagen degradation.  View on PubMed
  19. Kim KK, Sheppard D, Chapman HA TGF-ß1 Signaling and Tissue Fibrosis.  View on PubMed
  20. Stockis J, Liénart S, Colau D, Collignon A, Nishimura SL, Sheppard D, Coulie PG, Lucas S Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin aVß8.  View on PubMed

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