Paula M Oliver

faculty photo
Associate Professor of Pathology and Laboratory Medicine
Member, Abramson Cancer Center
Member, Institute for Immunology
Associate Professor, Children's Hospital of Philadelphia
Director, Protective Immunity and Immunopathology Affinity Group
Department: Pathology and Laboratory Medicine

Contact information
Cell 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
Graduate Group Affiliations
Education:
BS (Zoology)
North Carolina State University, 1989.
PhD (Pathology)
University of North Carolina at Chapel Hill, 1998.
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Description of 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

Description of Itmat Expertise

T cell differentiation
T cell function
Allergy
Autoimmunity
Ubiquitylation

Selected Publications

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: Ndfip1 restricts mTORC1 signaling and glycolysis in regulatory T cells to prevent autoinflammatory disease. Nature Communications in press 2017.

Layman AAK, Sprout SL, Phillips D, Oliver PM.: Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production. Sci Reports 4(7): 39649, Jan 2017.

Emily K Moser, Natania S Field and Paula M Oliver: Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia. Cellular & Molecular Immunology 13(epub), March 2017.

Awo Layman and Paula Oliver: Ubiquitin ligases and Dubs in CD4+ T cell effector fate choice and function. Journal of Immunology 196(10): 3975-82, May 2016.

Claire E. O'Leary, Christopher Riling, Lynn Spruce, Hua Ding, Suresh Kumar, Guoping Deng, Yuhong Liu, Steven H. Seeholzer, and Paula M. Oliver: Ndfip-mediated degradation of Jak1 tunes cytokine signaling to limit expansion of CD4+ effector T cells. Nature Communications 18(7): 11226, April 2016.

Claire E. O’Leary, Emma L. Lewis, and Paula M. Oliver: Ubiquitylation as a rheostat for TCR signaling: from targeted approaches towards global profiling. Frontiers in Immunology 16(6): 618, Dec 2015.

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: Itch WW domains inhibit its E3 ubiquitin ligase activity by blocking E2-E3 transthiolation. Journal of Biological Chemistry 290(39): 23875-87, Sept 2015.

Vanessa Kurzweil, Ami Laroche, and Paula M. Oliver: Increased peripheral IL-4 leads to an expanded virtual memory CD8+ population. Journal of Immunology 20(5): 524-30, June 2014

Allison M. Beal, Natalia Ramos-Hernandez, Chris R. Riling, Erin A. Nowelsky and Paula M. Oliver: TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentation. Nature Immunology 13(1): 77-85, January 2012 PMCID: PMC3542978.

Natalia Ramos-Hernández, Hilda E. Ramon, Allison M. Beal, Ami Laroche, Erin A. Dekleva and Paula M. Oliver: Ndfip1 enforces a requirement for CD28 co-stimulation by limiting IL-2 production. Journal of Immunology July (epub) 2013 PMCID: PMC3853121.

Ramon, HE, Riling,CR, Bradfield, J, Yang,B, Hakonarson, H, Oliver, PM: Ndfip1 regulates T cell-mediated gastrointestinal inflammation and susceptibility to inflammatory bowel disease. Mucosal Immunology 4(3): 314-24, May 2011 PMCID: PMC3905456.

Ramon HE, Beal AM, Liu Y, Worthen GS, and Oliver PM : The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines. Journal Immunology 188(8): 4023-31, April 2012 PMCID: PMC371391.

Deshmukh H., Liu Y., Menkiti O., Mei J., Dai N., O’Leary C., Oliver P.M., Kolls J., Weiser J., and Worthen G.S.: The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nature Medicine 20(5): 524-30, May 2014.

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Last updated: 05/04/2017
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