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Cells and Microbes

The students in the program approach Cells and Microbes from a variety of research angles. These topics include the molecular and cellular basis of immune responsiveness, molecular mechanisms of viral replication, host-pathogen interactions, and the control of viral, bacterial and parasitic infections.

Perturbing Nucleic Acid Sensing in Murine Models
to Identify Novel Mechanisms of Auto-immunity and Auto-inflammation

Ann Rothstein, Kate Fitzgerald Labs and Kevin M. Gao

 

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Dr. Rothstein has a long-standing interest in factors regulating the activation of autoreactive T and B cells. Her lab was the first group to demonstrate that members of the Toll-like receptor (TLR) family can detect mammalian nucleic acid ligands and that TLR9 or TLR7 play a key role in the activation of autoreactive B cells. Her current interests focus on the distinct roles of TLR7 and TLR9 in the pathogenesis of systemic autoimmune diseases, utilizing an inducible rapid onset model of cutaneous lupus. In related studies, she is exploring the role of cytosolic (eg. STING) and endosomal (TLR) sensors in models of autoinflammation resulting from constitutive activation of STING due to DNAseII deficiency or STING gain-of-function mutations. Additional projects revolve around the pro-apoptotic and pro-inflammatory functions of membrane-bound FasL and how these activities can be regulated by metalloproteinase-mediated cleavage of the extracellular FasL domain. Rothstein Lab

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Kevin joined the lab in November of 2018. His thesis research is centered on the regulation of immune cells by nucleic acid (NA) pattern recognition receptors (PRRs) in the pathogenesis of auto-immune and auto-inflammatory diseases. Because microbial and host-derived NA are both abundant, organisms restrain the immune system from acting non-discriminately and have developed strategies to discern inert signals from dangerous signals. Our labs utilize two murine models which perturb these control mechanisms: STING Associated Vasculopathy with onset in Infancy (SAVI), wherein a gain-of-function mutation in STING results in constitutive activation of the cytosolic dsDNA sensing pathway cGAS-STING, and DNaseII deficiency, wherein loss of an endosomal Dnase leads to impaired NA debris clearance. Using these models, Kevin hopes to identify mechanisms by which activation of NA sensors differentially regulates adaptive and innate immune cells, and how these mechanisms converge to coordinate multi-organ inflammation.
Kevin.Gao@umassmed.edu

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Dr. Fitzgerald’s has a long-standing interest in macrophages and innate immunity with a focus both on host-defense and sterile inflammation. Her group leverages cellular and molecular approaches to understand the mechanisms regulating inflammatory cytokine production. Her lab utilizes these multifaceted approaches to understand how the host responds to microbial infection and how the inflammatory process is regulated in order to avoid dangerous inflammatory responses and autoimmune disease. Her lab is particularly well-recognized for work on type I interferon gene regulation, TLR signaling pathways, inflammasome biology, long-non-coding RNAs and cytosolic DNA sensors. Ongoing projects include exploration of the molecular mechanisms that account for the autoinflammatory phenotype of mice and patients with STING gain-of-function mutations. The ultimate aim is to identify new paradigms in diagnosing and treating human disease through a deeper understanding of the molecular mechanisms regulating inflammation.
Fitzgerald Lab