Joel L. Pomerantz, Ph.D.

Research Overview

My laboratory is interested in the molecular mechanisms by which cells interpret signals from their environment that instruct them to proliferate, differentiate, or die by apoptosis. This process is of fundamental importance in the development and function of the immune system. The dysregulation of signal transduction underlies many diseases of the immune system including immunodeficiencies, autoimmunity, and cancers derived from immune cells. A particular focus of the lab is the regulation of NF-κB, a pleiotropic transcription factor that is required for normal innate and adaptive immunity and which is inappropriately activated in several types of human cancer. We have been studying how NF-κB is activated in B and T lymphocytes in response to antigen recognition by the T cell receptor (TCR) and B cell receptor (BCR) complexes. Recently we have characterized the molecular mechanisms by which a multi-domain adapter protein, CARD11, functions in TCR signaling to NF-κB. In response to antigen receptor engagement, CARD11 undergoes a transition from an inactive to an active protein scaffold, and recruits a cadre of signaling cofactors into a complex in a signal-responsive manner. Current research is aimed at understanding how the multiple domains of CARD11 function together to translate activating upstream signals from the antigen receptor into the coordinated signaling activity of associated cofactors. CARD11 has also been directly implicated in the dysregulated signaling to NF-κB that is a signature feature of a subtype of Diffuse Large B cell Lymphoma (DLBCL). This subtype of DLBCL requires constitutive NF-κB activation for oncogenic proliferation, and the knockdown of CARD11 in this lymphoma leads to apoptosis. Interestingly, several oncogenic mutations in CARD11 have been identified in human DLBCL. We are currently studying how the oncogenic CARD11 mutations result in hyperactive signaling to NF-κB. We are hopeful that a mechanistic understanding of these mutants might translate into the development of novel cancer therapeutics. In addition to the antigen receptor signaling pathway, we are also studying the regulation of NF-κB in other arms of the innate and adaptive immune system through the isolation and characterization of novel regulators of NF-κB activity. We have developed several novel expression-cloning approaches for identifying novel signaling molecules that either activate or inhibit NF-κB. Several novel signaling regulators are under current study. Other current projects include the study of novel regulators of the NFAT transcription factor, a key player in T cell activation and tolerance. It is our hope that the study of these signaling molecules will expand our understanding of how inflammatory and immune responses are controlled and they are dysregulated in human disease.

Cellular Stress and Cell Signaling | Genetics, Genomics and Gene Regulation | Immunology and Infectious Diseases

 

Lab Website

Pomerantz Lab – Lab Website

 

Selected Publications

Tamara O’Connor, Ph.D.

Background

Dr. Tamara O’Connor is an Assistant Professor of Biological Chemistry at the Johns Hopkins University School of Medicine and Director of Admission for the Graduate Program in Biological Chemistry. Dr. O’Connor’s research focuses on the molecular basis of infectious disease with a particular emphasis on the network of molecular interactions acting at the host-pathogen interface and pathogen evolution in natural reservoirs.

Dr. O’Connor received her Ph.D. in Biochemistry from McMaster University, Canada where she studied multicellular differentiation of the bacterium Streptomyces coelicolor with Dr. Justin Nodwell. She completed her postdoctoral training dissecting virulence mechanisms of the respiratory pathogen Legionella pneumophila with Dr. Ralph Isberg at Tufts University School of Medicine. She joined the Johns Hopkins faculty in 2013.

Dr. O’Connor is a member of the American Society for Microbiology and the American Society for Biochemistry and Molecular Biology. Dr. O’Connor received an Innovation Award from the Johns Hopkins University School of Medicine Discovery Fund, a Discovery Award from the Johns Hopkins University School of Medicine Fisher Center and was a Natalie V. Zucker Scholars Fellow and recipient of an Ontario Graduate Scholarship and a Bank of Montreal Graduate Scholarship in Science and Technology.

Centers and Institutes

Videos

Recent News Articles and Media Coverage

Research Interests

Microbial pathogenesis, pathogen evolution, antibiotics

Research Summary

The O’Connor lab studies bacterial pathogenesis focusing on defining the mechanisms by which bacterial pathogen establish infection, how they exploit host cell machinery to accomplish this, and how individual virulence proteins and their component pathways coordinately contribute to disease. In parallel, the O’Connor lab investigates how virulence strategies arise in environmental reservoirs as a consequence of bacterial interactions with protozoa and the role of these natural hosts in driving bacterial transmission and disease in humans. Using genetics, biochemistry, molecular and cellular biology, and functional genomics, the O’Connor lab examines the repertoires of virulence proteins required for growth in a broad assortment of hosts, how the network of molecular interactions differs between hosts, and the mechanisms by which bacterial pathogens cope with this variation.

O’Connor Lab – Lab website is currently under construction and will be available soon

Selected Publications

  • O’Connor TJ, Boyd D, Dorer M, Isberg RR (2012) Aggravating genetic interactions allow a solution to redundancy in a bacterial pathogen. Science 338:1440-1444
  • Boamah DK, Zhou G, Ensminger AW, O’Connor TJ (2017) From many hosts, one accidental pathogen: the diverse protozoan hosts of Legionella. Front Cell Infect Microbiol. 7:477
  • Ghosh S and O’Connor TJ (2017) Beyond paralogs: the multiple layers of redundancy in bacterial pathogenesis. Front Cell Infect Microbiol. 7:467
  • Park JM, Ghosh S, O’Connor TJ (2020) Combinatorial selection in environmental hosts drives the evolution of a human pathogen. Nat Microbiol. 5:599
  • Boamah D, Gilmore MC, Bourget S, Ghosh A, Hossain MJ, Vogel JP, Cava F, O’Connor TJ, (2023) Peptidoglycan deacetylation controls Type IV secretion and the intracellular survival of the bacterial pathogen Legionella pneumophila. Proc Natl Acad Sci USA. 120:e2119658120.
  • Ghosh S, Bandyopadhyay S, Smith DM, Adak S, Semenkovich CF, Nagy L, Wolfgang MJ, O’Connor TJ. (2023) Legionella usurps host cell lipids for vacuole expansion and bacterial growth. PLoS Pathogens. 20:e1011996.
  • Shin CJ and O’Connor TJ. (2024) Novel induction of broad-spectrum antibiotics by the human pathogen Legionella. mSphere. e0012024.

Honors

  • Fisher Center Discovery Program Award, Johns Hopkins University School of Medicine, 2018
  • Discovery Fund Innovation Award, Johns Hopkins University School of Medicine, 2014
  • Natalie V. Zucker Research Scholars Postdoctoral Fellow, 2009
  • Graduate Research Fellow, Ontario Graduate Scholarship Fund, 2003
  • Graduate Research Fellow, Bank of Montreal Graduate Scholarship in Science and Technology, 2002
  • Graduate Program Affiliations
  • Biological Chemistry (BC) Graduate Program
  • Biochemistry, Cellular and Molecular Biology (BCMB) Graduate Program
  • Immunology (IMM) Graduate Program
  • Cellular and Molecular Medicine (CMM) Graduate Program
  • Cross Disciplinary Graduate Program in Biomedical Sciences (XDBio)

Memberships

  • American Society for Microbiology
  • American Society for Biochemistry and Molecular Biology

Professional Activities

  • Department of Biological Chemistry Retreat Committee, Co-Chair, 2017-present
  • Department of Biological Chemistry Seminar Series, Chair, 2015-present
  • Biological Chemistry Graduate Program Admissions Committee, Member, 2013-present
  • Cross Disciplinary Gradate Program in Biomedical Sciences Admissions Committee, Member, 2018-present
  • Immunology Gradate Program Admissions Committee, Member, 2019-2020
  • Graduate Program in Biological Chemistry, Director, 2018 -present
  • Johns Hopkins Bug Super Group, Co-Founder, 2017-present
  • Society for Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS), Baltimore Chapter, Faculty Advisor, 2017-present
  • Frontiers in Cellular and Infection Microbiology, Associate Editor, 2022-present

Additional Training

  • Postdoctoral Fellowship, Tufts University School of Medicine, Boston, MA

Stephen Gould, Ph.D.

Affiliation: Professor of Biological Chemistry

Description of Research

Research in the Gould lab is focused on the intersection of cell biology, bioengineering, and human disease.

Mechanisms of exosome biogenesis

Exosomes are small secreted vesicles of ~100 nm in size that play critical roles in human health and disease. We study the molecular mechanisms of exosome biogenesis by interrogating the biogenesis, intracellular trafficking, and vesicular secretion of highly enriched exosome cargo proteins, as well as viral proteins that use the hosts’ exosome biogenesis pathways for the formation of infectious viruses. Most recently, we’ve discovered that exosome marker proteins all bud primarily from the plasma membrane, and moreover, that endocytosis of exosome marker proteins from the plasma membrane greatly inhibits their vesicular secretion. These results re-write our understanding of exosome biogenesis by showing that it occurs primarily by direct budding from the plasma membrane, with only minor contributions from exocytosis of internal vesicles (Ai et al. Science Advances 2024, https://www.science.org/doi/10.1126/sciadv.adi9156).

Cell and exosome engineering

As the only bionormal nanovesicle, exosomes are an ideal delivery vehicle for vaccines, biologics, and drugs. Our laboratory uses our latest advances in exosome biogenesis to create proteins that are efficiently loaded into exosomes and confer unique properties on recombinantly engineered exosomes, including induction of immune responses, inhibition of angiogenesis, and other biomedically important activities. We then drive the high-level production of recombinant exosome-targeted proteins using new, highly restrictive antibiotic resistance genes that allow us to rapidly create cell lines that express the highest possible levels of recombinant proteins.

Synthetic signaling systems

Together with Dr. Michael Caterina’s lab, we’ve invented synthetic signaling systems that convert pathogenic signaling pathways into tunable, negative feedback loops that attenuate their pathogenic effects. These genetically-encoded tools are designed to ameliorate chronic diseases, with our primary focus on developing a safe and effective treatment for chronic pain.