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InflammAct

Activation and Regulation of the NLRP3 Inflammasome

 

Principal Investigator

Prof. Dr. Eicke Latz
Institute of Innate Immunity
Sigmund-Freud-Str. 25
53127 Bonn

 

Abstract

The innate immune system protects the host from infections, detects and repairs tissue damage and functions to maintain tissue homeostasis. Several families of signaling receptors can recognize microbial substances or altered host molecules and orchestrate a coordinated inflammatory response. Inflammasomes are signaling platforms that control proteolytic activation of highly proinflammatory cytokines of the IL-1β family and thus, are relevant for infection control but are also implicated in mediating inflammatory diseases. In addition to recognizing several foreign signals, the NLRP3 inflammasome can sense sterile tissue damage, and a number of endogenous danger signals that appear in many common chronic inflammatory conditions. NLRP3 can be triggered by material released from dying cells and aggregated or crystalline substances, and its activation has been implicated in the pathogenesis of prevalent diseases in Western societies, including type 2 diabetes, chronic obstructive pulmonary disease, atherosclerosis and Alzheimer’s disease. The NLRP3 inflammasome can be activated by diverse signals, however, the molecular mechanisms that lead to NLRP3 inflammasome activation remain poorly understood. Using chemical biology screens, as well as proteomics analysis, we have identified that NLRP3 activity can be post-tranlationally regulated by phosphorylation and ubiquitination.

In this proposal we aim to identify the enzymes and signaling mechanisms leading to NLRP3 activation. In an integrated, multidisciplinary approach, we will employ chemical biology screening to identify novel targets that act in the regulation of NLRP3 and will describe the NLRP3 interactome in response to various triggers. The data obtained by these approaches will be analyzed by bioinformatics, and the signaling mechanisms identified will be subsequently confirmed using RNA interference and gain-of-function studies. Utilizing a range of biochemical, biophysical and immunological techniques, we will determine the mechanisms by which the identified molecules can activate the NLRP3 inflammasome and assess their physiological relevance in in vitro and in vivo models of inflammation.

 

Laufzeit

01.07.2014 - 30.06.2019

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