PEOPLE

Paula M. Oliver, PhD

Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact InformationCell Pathology Division 816F/ARC
Children’s Hospital of Philadelphia
The University of Pennsylvania
3615 Civic Center Blvd. 816F/ARC
Philadelphia, PA 19104
Office: 267-426-2839
Fax: 267-426-5165

Email: paulao@mail.med.upenn.edu

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Research Interest
Our focus is on defining new mechanisms that regulate immune cell activation and protective immune responses. Our goal is to use this information to design therapies with which to treat the immune-mediated pathologies found in autoimmune and allergic disease.

Research Summary
During pathogenic infection, immune cells collaborate to remove invading organisms while minimizing collateral damage. Immune cells must continually respond to external stimuli, and adjust their levels of key regulatory proteins, to transition between poised and active states. To accomplish this, immune cells can increase protein production, modify existing proteins, or change their rate of protein degradation. ‘Tagging’ a protein with ubiquitin is a post-translational modification that can improve interactions between proteins to promote signaling, or initiate protein degradation. Ubiquitylation is regulated by enzymes that add (E3 ubiquitin ligases) or subtract (deubiquitylating enzymes) ubiquitin from substrates. We use systems biology approaches to define changes in ubiquitylation as activation states change, and to identify ubiquitin ligases that regulate immune cell fate. We combine this information with genetic, cellular and biochemical approaches to define how ubiquitin enzymes regulate immune cell biology.

One area of focus in the lab has centered on catalytic HECT-type E3 ubiquitin ligases of the Nedd4-family. The 9 members of this family that exist in mammalian cells evolved from a common yeast progenitor known as RSP5. We have identified a small family of membrane tethered adaptors, Ndfip1 and Ndfip2, that activate several Nedd4-family E3s. Additionally, we have determined that these adaptors regulate T cell activation, CD4 differentiation and effector function, and Treg cell metabolism and lineage stability. We combined this information on biologic function with biochemical data in which we defined precisely how these adaptors activate the enzymatic activity of Nedd4-family ligases, and are now using this information in the rational design of therapeutics. Based on our data, such therapeutics will be particularly useful in the treatment of autoimmune and/or allergic disease.

Our recent work has employed systems biology approaches in which we intrgrated transcriptome, proteome and ubiquitome information to identify Cullin E3 ubiquitin ligases that are particularly active as T cells transition from resting to activated states. We are now generating genetic models in which to test the the biologic relevance of these ligases in protective immune responses. We are now poised to define how cullin ligases form distinct ubiquitin complexes in T cells or other immune cells, and the unique set of substrates targeted by these complexes. Once we answer these questions we will be positioned to translate this information into new therapies for patients.


Lab Personnel

Emily Moser PhD – Postdoctoral Fellow
Awo Layman – MD/PhD Student (IGG)
Natania Field – MD/PhD Student (MVP)
Asif Dar PhD – Postdoctoral Fellow
Joseph Dybas PhD – Postdoctoral Fellow
Yan Chen PhD – Technician
Keisuke Sawada – Technician
Jennifer Roof – Undergraduate
Varshini Gali - Undergraduate



Itmat Expertise

T cell differentiation
T cell function
Allergy
Autoimmunity
Ubiquitylation

Graduate Groups

Cell and Molecular Biology
Immunology

Education

BS (Zoology), North Carolina State University, 1989
PhD (Pathology), University of North Carolina at Chapel Hill, 1998

Specialty Certification

Postgraduate Training

Postdoctoral Fellowship-Immunology, National Jewish Medical and Research Center, 1998-2002
Postdoctoral Fellowship - Immunology, HHMI National Jewish Medical and Research Center, 2002-2007

Awards and Honors

NIH Postdoctoral Training Grant, 1998-1999
Leukemia and Lymphoma Society Fellow, 1999-2002
Christopher and Peter Gitzen Fellowship, 2000-2001
Howard Hughes Medical Institute, 2002-2005
Foerderer Award, 2008-2009
Chair Research Award, 2009-2010
American Asthma Association Scholars Award, 2013-2016
ITMAT Award, 2013-2015

Memberships and Professional Organizations

National Jewish Center, 2002 - 2003
American Association of Immunologists, 2009 - present
Arthritis Foundation post-doctoral training grants, 2010 - 2010
NIH Immunology Fellowships and Area Study Section, 2012 - 2014
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2012 - 2014
Faculty 1000, 2012 - present
Annual Ubiquitin Research in Drug Discovery Conference, 2012 - 2013
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2014 - Present

Web Links


Selected Publications

Ndfip1 restricts mTORC1 signaling and glycolysis in regulatory T cells to prevent autoinflammatory disease.

Awo Akosua K. Layman, Guoping Deng, Claire E. O’Leary, Samuel Tadros, Rajan M. Thomas, Joseph M. Dybas, Emily K. Moser, Andrew D. Wells, Nicolai M. Doliba & Paula M. Oliver, Nature Communications, 2017

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production.

Layman AAK, Sprout SL, Phillips D, Oliver PM., Sci Reports 4(7): 39649, 2017

Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia

Emily K Moser, Natania S Field and Paula M Oliver, Cellular & Molecular Immunology 13(epub): , 2017, PMID:28260794

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Ubiquitin ligases and Dubs in CD4+ T cell effector fate choice and function

Awo Layman and Paula Oliver, Journal of Immunology 196(10): 3975-82, 2016

Ndfip-mediated degradation of Jak1 tunes cytokine signaling to limit expansion of CD4+ effector T cells

Claire E. O'Leary, Christopher Riling, Lynn Spruce, Hua Ding, Suresh Kumar, Guoping Deng, Yuhong Liu, Steven H. Seeholzer, and Paula M. Oliver, Nature Communications 18(7): 11226, 2016

Ubiquitylation as a rheostat for TCR signaling: from targeted approaches towards global profiling

Claire E. O’Leary, Emma L. Lewis, and Paula M. Oliver, Frontiers in Immunology 16(6): 618, 2015

Itch WW domains inhibit its E3 ubiquitin ligase activity by blocking E2-E3 transthiolation

Christopher Riling, Hari Kamadurai, Suresh Kumar, Claire E. O’Leary, Kuen-Phon Wu, Erica E. Manion, Mingjie Ying, Brenda A. Schulmanb, and Paula M. Oliver, Journal of Biological Chemistry 290(39): 23875-87, 2015

Increased peripheral IL-4 leads to an expanded virtual memory CD8+ population

Vanessa Kurzweil, Ami Laroche, and Paula M. Oliver, Journal of Immunology 20(5): 524-30, 2014, PMID:24747744

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TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentation

Allison M. Beal, Natalia Ramos-Hernandez, Chris R. Riling, Erin A. Nowelsky and Paula M. Oliver, Nature Immunology 13(1): 77-85, 2012 PMCID: PMC3542978

Ndfip1 enforces a requirement for CD28 co-stimulation by limiting IL-2 production.

Natalia Ramos-Hernández, Hilda E. Ramon, Allison M. Beal, Ami Laroche, Erin A. Dekleva and Paula M. Oliver, Journal of Immunology, 2013 PMCID: PMC3853121

The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice.

Deshmukh H., Liu Y., Menkiti O., Mei J., Dai N., O’Leary C., Oliver P.M., Kolls J., Weiser J., and Worthen G.S., Nature Medicine 20(5): 524-30, 2014

Ndfip1 regulates T cell-mediated gastrointestinal inflammation and susceptibility to inflammatory bowel disease

Ramon, HE, Riling,CR, Bradfield, J, Yang,B, Hakonarson, H, Oliver, PM, Mucosal Immunology 4(3): 314-24, 2011 PMCID: PMC3905456

The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines

Ramon HE, Beal AM, Liu Y, Worthen GS, and Oliver PM, Journal Immunology 188(8): 4023-31, 2012 PMCID: PMC371391