Inflammasome activation in autoinflammatory disease

Inflammasome activation in autoinflammatory disease

Project details

Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory disease associated with infection and immune cell-driven hyperinflammation. The five-year survival rate for primary (genetically inherited) HLH is only 21-26 per cent, which underscores the inadequacy of current therapies. Research suggests that blocking the inflammasome-activated proteins, IL-1b and/or IL-18, may be of therapeutic benefit. Despite this, it is not understood which HLH-associated genetic lesions trigger pathological inflammasome activity, nor which inflammasome sensor proteins are activated in HLH.

This project will use CRISPR/Cas9 gene targeting and relevant HLH models to establish the molecular mechanism by which inflammasomes are activated by distinct genetic lesions that predispose to HLH. These studies will allow accurate predictions as to which patients will respond to anti-inflammasome therapy and, importantly, will identify urgently needed drug targets.

About our research group

Our laboratory studies the receptors and signaling networks that cause cell death and promote inflammatory cytokine production. These processes, often connected, are required to protect against microbial infection and repair damaged tissues but can also be pathologically activated in many diseases.

Using gene knockout disease models, mass-spectrometry, and genetic screening, we have identified

i) novel inflammatory regulators (doi: 10.1038/cdd.2017.173),

ii) signaling pathways that trigger inflammasome activation (doi: 10.1073/pnas.1613305114; doi: 10.1016/j.celrep.2018.10.103),

iii) mechanisms to induce cell death to protect against infection (doi: 10.1038/nmicrobiol.2015.34),

iii) unique pathways that contribute to gout (doi: 10.4049/jimmunol.1900228), and

iv) the molecular mechanisms by which genetic lesions can trigger hereditary autoinflammatory disease (doi: 10.1016/j.celrep.2017.06.073; doi: 10.1038/ncomms7282).

Researchers:

Dr James Vince

Dr James Vince in a laboratory
Dr
James
Vince
Laboratory Head

Project Type: