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Inflammation/Immunology

The role of the immune system and contribution of inflammation to cardiovascular disease, atherosclerosis, demyelinating disease, cancer and host response to pathogens is a major area of interest in the department. Several groups are interested in inflammatory pathways associated with cardiovascular damage and repair including the development of fibrosis.

Learn more about our work below.

 Deyu Fang Lab

Studying molecular networks in the regulation of immune response and autoimmunity

Research Interests

Our research goal is to identify the therapeutic molecular targets for the treatment of autoimmune diseases particularly of rheumatoid arthritis (RA) and type 1 diabetes (T1D).

In our laboratory, we use genetic, proteomic, molecular biology and immunological approaches to dissect the molecular networks underlying the regulation of immune response and autoimmunity. Several specific genes that are critical for immune regulation and autoimmune diseases have been identified in our laboratory. Small molecules that modulate the functions of these newly identified genes can potentially be used to treat type 1 diabetes and rheumatoid arthritis.

The current ongoing research projects, in my laboratory are:

1. Sirt1, a type-iii histone deacetylase, is required for immune tolerance.
2. The ubiquitin E3 ligase Synoviolin, is a therapeutic target for RA.
3. The tyrosine kinase c-Abl in T-cell differentiation and allergic lung inflammation.
4. The roles of RoxP3 in regulatory T cells.
5. Ubiquitination in aging and autoimmunity.
6. Novel microRNAs in immune tolerance and autoimmunity.

For more information, visit Dr. Deyu Fang's faculty profile or laboratory site.

Publications

See Dr. Fang's publications in PubMed.

Contact

Dr. Fang

 William Muller Lab

Focusing on the emigration of leukocytes across vascular endothelial cells in the process of inflammation

Research Description

Most diseases are due to or involve a significant component of inflammation. My lab studies the inflammatory response at the cellular and molecular level. We are focused on the process of diapedesis, the "point of no return" in inflammation where leukocytes squeeze between tightly apposed endothelial cells to enter the site of inflammation. We have identified and cloned several molecules that are critical to the process of diapedesis (PECAM (CD31), CD99, and VE-cadherin) and are studying how they regulate the inflammatory response using in vitro and in vivo models. We have recently described the Lateral Border Recycling Compartment, a novel para-junctional organelle that contains PECAM and CD99 and is critical for diapedesis to occur. We are currently investigating how this compartment regulates diapedesis in the hope of finding novel and highly specific targets for anti-inflammatory therapy.

The “holy grail” of therapy is to develop selective anti-inflammatory agents that block pathologic inflammation without interfering with the body’s ability to fight off infections or heal wounds.  By understanding how endothelial cells at the site of inflammation regulate leukocyte diapedesis, we are hoping to do just that.  We have identified several molecules critical for diapedesis in acute and chronic inflammatory settings that can be genetically deleted or actively blocked to markedly inhibit clinical symptoms (e.g. in a mouse model of multiple sclerosis) and tissue damage (e.g. in a mouse model of myocardial infarction) without impairing the normal growth, development, and health of these mice.  Our inflammatory models include atherosclerosis, myocardial infarction, ischemia/reperfusion injury, stroke, dermatitis, multiple sclerosis, peritonitis, and rheumatoid arthritis. We are also using 4-dimensional intravital microscopy to view the inflammatory response in real time in living animals.

Basic questions/issues that the work seeks to address:
  • What are the molecular mechanisms and signaling pathways that endothelial cells use to regulate the inflammatory response?
  • How can we therapeutically treat inflammatory diseases without compromising the ability of the immune system to respond to new threats?
  • Do circulating tumor cells use the same mechanisms as leukocytes to cross blood vessels when they metastasize?

Our Facilities

We have a high-resolution Perkin Elmer ULTRAVIEW Vox System spinning disk laser confocal microscope in the upright configuration on an Olympus BX51WI fixed stage in my laboratory designed for intravital microscopy.  We can image the ongoing inflammatory response and response to our drugs in real time in anesthetized mice with unprecedented temporal and spatial resolutions.  We presently image inflammation in the cremaster muscle, intestine, and brain.

Of interest to History of Science buffs, we have the original Zeiss Ultrafot II microscope used to film the first movies of neutrophils ingesting bacteria. As you might expect from something built by Zeiss in the first half of the 20th century, the optics are still fantastic and we use it in our daily work.

Our Successes

Recently we made two major discoveries in endothelial cell inflammatory signaling: Identification of TRPC6 as the cation channel responsible for the endothelial cell calcium flux required for transmigration and description of the CD99 signaling pathway.  Both had eluded discovery for decades.

  • Watson, R.L., J. Buck, L.R. Levin, R.C. Winger, J. Wang, H. Arase, and W.A. Muller. 2015. Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte   transendothelial migration. J. Exp. Med. 212:1021-1041.
  • Weber, E.W., F. Han, M. Tauseef, L. Birnbaumer, D. Mehta, and W.A. Muller. 2015. TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-1899. PMID:    26392222

Recent Awards

  • AAAS Fellow, elected 2010
  • Rous-Whipple Award, American Society for Investigative Pathology, 2013
  • Ramzi Cotran Memorial Lecture, Brigham and Women’s Hospital, 2014
  • Karl Landsteiner Lecture, Sanquin Research Center, Amsterdam, Netherlands, 2016
  • Member, Faculty of 1000 Leukocyte Development Section
  • American Society for Investigative Pathology (ASIP) Council
  • ASIP Research and Science Policy Committee Chair
  • North American Vascular Biology Organization (NAVBO) Secretary-Treasurer

Grants Won

  • NIH R01 HL046849-26 William A. Muller                     08/01/91 – 05/31/20

    The Roles of Endothelial PECAM and the LBRC in Leukocyte Transmigration

    This study investigates how PECAM-1 and the LBRC regulate transmigration.  We will investigate how PECAM ligation on endothelial cells activates TRPC6 to promote the calcium flux necessary for transmigration (Aim I).  We will identify how endothelial IQGAP1 regulates transmigration by regulating targeted recycling of the LBRC (Aim II).  We will identify how kinesin light chain 1 variant 1 facilitates movement of the LBRC during targeted recycling (Aim III).  All of these Aims include mechanistic studies in vitro and validation studies in vivo using mouse models of ischemia/reperfusion injury in acute inflammation and myocardial infarction.

  • NIH R01 HL064774-16 William A. Muller                     04/01/00 – 08/31/20

    Beyond PECAM:  Mechanisms of Transendothelial Migration

    This study investigates the role of PECAM, CD99L2, and CD99 in transendothelial migration.  Aim I will test the hypothesis that leukocytes control the molecular order of transmigration by polarizing PECAM on their leading edge and CD99 on the trailing edge during transmigration.  Aim II will identify the signaling mechanisms by which CD99L2 regulates transmigration.  Aim III will identify the signaling mechanisms by which CD99 regulates targeted recycling of the LBRC and transmigration downstream of Protein Kinase A.  All Aims have in vitro mechanistic studies and in vivo validation studies using intravital microscopy in the cremaster muscle circulation and a murine model of ischemia/reperfusion injury in myocardial infarction.

For more information, visit the faculty profile of William A Muller, MD, PhD

Publications

View Dr. Muller's publications at PubMed

Staff

Research Assistant Professors

Assistant Professor (Department of Neurology) Research Resident (PSTP) Graduate Students Research Associates Technical Staff

Contact

Bill Muller

Office: Ward Building, Room 3-126
303 East Chicago Avenue
Chicago, IL 60611-3008

Phone: (312) 503-0436
Fax: (312) 503-8249
E-mail:  wamuller@northwestern.edu

Lab: Ward Building 3-070 and 3-031
Lab Phone: (312) 503-5200
Lab Fax: (312) 503-2630

 Ronen Sumagin Lab

Contributions of immune cell-mediated inflammation to development and progression of colorectal cancers

Research Description

Immune cells are critical for host defense, however immune cell infiltration of mucosal surfaces under the conditions of inflammation leads to significant alteration of the tissue homeostasis. This includes restructuring of the extracellular matrix and alterations in cell-to-cell adhesions. Particularly, immune cell-mediated disruption of junctional adhesion complexes, which otherwise regulate epithelial cell polarity, migration, proliferation and differentiation can facilitate both tumorigenesis and cancer metastasis. Our research thus focuses on understanding the mechanisms governing leukocyte induced tissue injury and disruption of epithelial integrity as potential risk factors for tumor formation, growth and tissue dissemination.

For publication information see PubMed and for more information see Dr. Sumagin's faculty profile page or laboratory site.

Contact information

Ronen Sumagin, PhD
Assistant Professor in Pathology
312-503-8144
Email:  ronen.sumagin@northwestern.edu

 Benjamin Thomson Lab

Links between endothelial function and vision

Research Interests

Endothelial dysfunction is a major cause of vision loss, playing a key role in diseases including age-related macular degeneration, diabetic retinopathy and glaucoma. Using mouse genetics, animal disease models and a combination of single cell RNA-sequencing and histological approaches, our lab is focused on understanding the role of the vasculature in these diseases, including glaucoma and age related macular degeneration. By elucidating molecular connections between endothelial dysfunction and vision loss, we aim to identify novel therapeutic targets and translate these discoveries into patient care.

While endothelial dysfunction is a component of many eye diseases, the importance of ocular vasculature in age related macular degeneration is widely understood and is the basis for the life-altering anti-VEGF therapies that target choroidal neovascularization associated with these conditions. The choroid and choriocapillaris (CC) form a unique vascular bed in the back of the eye that is vital for maintenance of the retinal photoreceptors and retinal pigment epithelium (RPE). In addition to the well-described link with AMD, choroidal dysfunction is tied to the poorly understood spectrum of pachychoroid diseases including polypoidal choroidal vasculopathy (PCV), which can lead to irreversible loss of vision. Despite their clinical impact, little is known about pathogenesis or optimal treatment of PCV and other pachychoroid diseases, or why some patients with defects in the choroidal vasculature develop geographic atrophy or neovascular AMD and others PCV. Ongoing research in our lab seeks to answer this question, using animal models, single cell RNA sequencing and in vivo imaging to gain mechanistic insights into pachychoroid biology, understand mechanisms by which choriocapillaris attenuation lead to choroidal dysfunction, and identify genes and pathways which can be targeted for future therapies. 

Publications

For additional information, visit the faculty profile of Dr. Thomson

View Dr. Thomson's publications at PubMed

Contact

Contact Dr. Thomson

 

Contact Us

Deyu Fang

Professor of Pathology (Experimental Pathology)

William A Muller

Professor of Pathology (Experimental Pathology) and Pathology (Autopsy)

Ronen Sumagin

Associate Professor of Pathology (Experimental Pathology)

Edward Benjamin Thorp

Associate Professor of Pathology (Experimental Pathology) and Pediatrics

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