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Northwestern University Feinberg School of Medicine
Department of Medicine
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Labs

Learn more about the work conducted by labs within our division.

 

 Harris Perlman Lab

The Perlman Lab centers on rheumatic disease, particularly the impact that macrophages play in pathogenesis of rheumatic disease.

Macrophages have emerged as key players in the development of inflammation and fibrosis in central target organs including the synovium, kidney and lung during the pathogenesis and remission of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), respectively. Macrophages also contribute to the co-morbidities associated with these diseases including atherosclerosis and obesity. We observed marked heterogeneity in the macrophage population within diseased tissues that is dependent on their origin (embryonic vs. bone marrow derived), target organ and microenvironment. Moreover, these macrophages are extremely plastic and can alter their phenotype throughout the course of disease. Based on our data we developed a central hypothesis that during the initiation and early progression phase of disease tissue resident macrophages that normally function to maintain tolerance to local antigens, are overwhelmed by recruited pro-inflammatory or pro-fibrotic monocyte derived macrophages or pro-inflammatory dendritic cells depending on the target organ and environmental milieu. As the disease progresses to the chronic phase, however, the recruited macrophages acquire characteristics reminiscent of tissue resident macrophages while retaining a pro-inflammatory and pro-fibrotic phenotype, resulting in failed resolution of inflammation and progressive tissue destruction and fibrosis. The data anticipated from our projects would be the first to demonstrate a direct linkage of macrophage ontogeny and activation to disease activity and tissue damage. In addition, our studies allow us to explore commonalities in macrophage function between diseases that could lead to broad therapeutic interventions. In our state-of-the-art murine models we use cutting-edge technologies that we developed including micro-MRI, CT and SPECT to evaluate joint inflammation, bone destruction and lung fibrosis, Luminex-based gene arrays and multiparameter flow cytometry/sorting, whole population RNA seq and single cell RNA Seq and Chip-seq. We will cross-reference these data with those we will obtain through the AMP programs, which examine macrophage heterogeneity in the synovium and kidney from patients with rheumatic disease. This will allow us to rapidly move to functional analyses of relevant pathways and testing of new therapeutic strategies in the mouse models. I believe that our data has the potential to be paradigm shifting and transformative for the field of rheumatic disease.

Publications

View Dr. Perlman's publications at PubMed

For more information related to the Perlman Lab, or to connect with us, please see Harris R Perlman’s, PhD, profile.

Contact

Contact Dr. Perlman at 312-503-8003 or the Perlman Lab at 312-503-1933.

 Richard Pope Lab

The Pope Lab studies the biology of macrophages in the pathogenesis of rheumatoid arthritis (RA). These studies are directed at defining the mechanisms that promote resistance to apoptosis or programmed cell death and the role of endogenous Toll Like Receptor (TLR) ligands in the pathogenesis of RA.

Our laboratory has identified the upregulation of the anti-apoptotic protein, Flice Like Inhibitory Protein (FLIP), during monocyte to macrophage differentiation. They have demonstrated that FLIP is highly expressed in the rheumatoid joint and is responsible for protecting RA macrophages from Fas-mediated apoptosis. These studies have been extended to examine the in vivo relevance of FLIP to macrophage biology. Mice with FLIP conditionally deleted in myeloid cells are not capable of developing macrophages. The relevance of these observations to chronic inflammatory arthritis is currently under investigation. Since macrophages are critical to the pathogenesis of RA, future studies will focus on macrophage specific FLIP as a therapeutic target in RA.

Additional studies in the laboratory are focusing on the role of endogenous TLR ligands as potential contributors to the persistent activation of macrophages in the RA joint. The Pope laboratory has identified an endoplasmic reticulum (ER) localized protein called gp96, which binds to TLRs within ER of macrophages and correctly transports them to the cell membrane or endosome. In patients with RA, gp96 is highly increased in RA synovial tissue, particularly in macrophages, and is found in RA synovial fluid in high concentrations. gp96 binds to the extracellular domains of TLR2 and TLR4. Both recombinant gp96 and gp96 present in the RA synovial fluid is capable of activating TLR2 and to a lesser degree TLR4. Ongoing studies in the laboratory are further characterizing the mechanisms by which gp96 and other endogenous TLR ligands might contribute to the pathogenesis of RA employing in vitro studies utilizing cells isolated from the joints of patients with RA and experimental murine models of RA

Additional studies are ongoing in the laboratory to further identify and define the potential clinical relevance of endogenous TLR ligands in the RA joint employing three approaches which are dependent upon binding to endogenous ligands to TLRs. These approaches include the use of recombinant IgG Fc-TLR2 and IgG Fc-TLR4 to pull down TLR ligands from cells isolated from the RA joint; the use of HEK-TLR2 and HEK-TLR4 cells to bind endogenous TLR ligands in RA synovial fluid which will be identified employing a proteomics approach and utilizing a yeast 2 hybrid system where mRNA from inflammatory RA synovial tissue has been employed to develop the bait, while the extracellular domains to TLR2 and TLR4 are being used as the prey. Each of these approaches have identified candidate molecules which are being further characterized for a potential role in the pathogenesis of RA.

Publications

View Dr. Pope's publications at PubMed

For more information related to the Pope Lab’s work, please see Richard M. Pope’s, MD, profile.

Contact

Contact Dr. Pope at 312-503-8003 or the Pope Lab at 312-908-1965

 John Varga Lab

Research in our laboratory focuses on the mechanisms of fibrosis and inflammation/autoimmunity in human diseases.

Our research integrates genetic and genomic approaches with experimental studies using cell-based systems, organ cultures and animal models. In particular, we are studying regulation of fibroblast activation, mesenchymal cell differentiation and the cross-talk between macrophages, monocytes and stromal cells and the role of innate immune signaling, in aberrant tissue remodeling and wound healing.

Fibrosis is a non-specific response that occurs in reaction to any type of chronic or persistent tissue injury. While acute fibrogenesis is beneficial for rapidly restoring tissue homeostasis and regeneration, chronic or deregulated responses to injury lead to scar. Fibrosis is now one of the a leading causes of deaths worldwide. Therefore, an important goal is to define the cells, metabolic states, molecules and signaling pathways that regulate tissue repair and how genetic and epigenetic modifications in these pathways result in chronic fibrosis. We focus on fibrotic diseases affecting the skin, lungs and heart.

We are investigating the molecular mechanisms that control activation of fibroblasts and myofibroblasts and the role of innate immunity, toll-like receptors and related pattern recognition receptors and the cross-talk among monocytes, macrophages, dendritic cells and adipocyte progenitor cells and  mesenchymal stromal cells. In addition, studies are investigating the origins of activated stromal cells, using transgenic lineage tracing approaches. We focus on pathways implicated in large-scale genetic studies are candidates based on their association with scleroderma, pulmonary fibrosis and chronic inflammation.

We routinely employ molecular, cellular, biochemical and genetic approaches in our studies, along with omics approaches such as genomewide transcriptomics and GWAS, proteomics and candidate gene approaches. We make extensive use of human samples such as skin biopsies, lung tissue, explanted fibroblasts and blood cells and animal models of disease. We are also developing organoid approaches to model fibrosis and repair in human skin. Many of our studies focus on the discovery of targeted therapies and of biomarkers for predicting disease severity, activity and response to therapy in genetically diverse human populations.

Publications

View Dr. Varga's publications at PubMed

For more information visit Dr. Varga's faculty profile page

Contact

Contact Dr. Varga at 312-503-8003 or the Varga Lab at 312-503-0498

 Deborah Winter Lab

Computational immunology - Using genomic approaches to study rheumatic disease.

Research Description

The goal of the Winter Lab of Functional Genomics is to apply genomic approaches to study rheumatic disease. Led by Dr. Deborah Winter, a computational immunologist, we employ the latest technologies for assays, such as RNA-seq, ChIP-seq, ATAC-seq and single cell expression, to profile the transcriptional and epigenomic profiles of immune cells in health and disease. Our goal is to define the underlying regulatory networks and understanding how they respond to challenge, illness and injury. We are particularly interested in the role of macrophages in diseases such as scleroderma, rheumatoid arthritis and lupus. Previous research has addressed the impact of the tissue environment on resident macrophages and the role of microglia, CNS-resident macrophages, in brain development. Our research combines molecular and systems biology, biotechnology, clinical applications and computer science. We use both mouse models and patient samples to help us understand and test different systems. We are committed to high standards of analysis and are continually updating and training in innovative computational techniques. We are currently recruiting highly motivated individuals to join the lab.

For more information, visit the faculty profile of Dr. Winter.

Publications

View Dr. Winter's publications at PubMed

Contact Us

Contact Dr. Winter at  312-503-0535 or by email.

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