Dean Sheppard, MD

Professor & Chief
Department of Medicine
Lung Biology Center
+1 415 514-4269

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 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 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 in the lung, skin, kidney, liver and central nervous system and is exploring the potential of engineering T cells for local delivery of novel therapeutics to fibrotic organs.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Immunology
Research Summary: 
In vivo function of integrins and molecular basis of lung diseases

Websites

Featured Publications: 

Unexpected Role for Adaptive aßTh17 Cells in Acute Respiratory Distress Syndrome.

Journal of immunology (Baltimore, Md. : 1950)

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

The avß1 integrin plays a critical in vivo role in tissue fibrosis.

Science translational medicine

Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, Sheppard D

TGF-ß activation and function in immunity.

Annual review of immunology

Travis MA, Sheppard D

Targeting of av integrin identifies a core molecular pathway that regulates fibrosis in several organs.

Nature medicine

Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D

Integrin a9ß1 in airway smooth muscle suppresses exaggerated airway narrowing.

The Journal of clinical investigation

Chen C, Kudo M, Rutaganira F, Takano H, Lee C, Atakilit A, Robinett KS, Uede T, Wolters PJ, Shokat KM, Huang X, Sheppard D

IL-17A produced by aß T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction.

Nature medicine

Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X, Li JT, Atabai K, Huang X, Sheppard D

Expression of avß8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice.

The Journal of clinical investigation

Melton AC, Bailey-Bucktrout SL, Travis MA, Fife BT, Bluestone JA, Sheppard D

Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice.

Nature

Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D

Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema.

Nature

Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A, Sheppard D

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.

Cell

Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D