Jonathan C. Kagan
Ancient signaling pathways lie at the base of the initiation of immunity, serving to transmit signals from Pattern Recognition Receptors (PRRs) to trigger the activation of anti-microbial defenses. All PRRs, which evolved to detect potentially pathogenic microorganisms, operate by following two cellular rules: 1) these receptors must activate cytosolic signaling with extremely fast kinetics (within seconds of ligand binding) 2) these receptors must survey multiple cellular compartments, yet still recruit a common set of signaling proteins to each location. How does a signaling network develop that has properties of near immediate responsiveness, yet the flexibility to signal from multiple locations?
While most research on immune signal transduction focuses on the effector functions of signaling proteins, we are interested in understanding how these proteins are organized in the cytosol to promote both rapid responses and the flexibility of signaling locale. Using the Toll-like Receptor (TLR) family of PRRs as a model, we seek to explain the operation of cytosolic signaling proteins that function in immune defense.
TLRs promote the initiation of both innate and adaptive immunity to infectious microorganisms and as such, the regulation of TLR signaling lies at the base of important issues in human health, such as the generation of effective vaccines, autoimmunity, and even cancer.
Understanding the fundamental cellular principles that control TLR signaling will likely reveal important insight into these problems and will open up new possibilities for treatment of common ailments that affect humanity.
Current projects in the lab focus on addressing the following problems:
1. How are TLR signaling proteins delivered to the appropriate cellular locations to promote signal transduction?
2. What are the biochemical properties of TLR-induced signaling complexes?
3. How does the innate immune response deal with commensal bacteria in the intestine?
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