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
Faculty 1000, 2012 - present
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2012 - 2014
NIH Immunology Fellowships and Area Study Section, 2012 - 2014
Annual Ubiquitin Research in Drug Discovery Conference, 2012 - 2013
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2014 - Present
NIH Special Emphasis Panel, 2017 - 2017

Web Links

Selected Publications