Chronic inflammation is causally linked to cancer development and most cancers contain an inflammatory infiltrate that is hijacked by tumour cells to promote angiogenesis, tissue invasion and cell proliferation. Moreover, autoimmune diseases with a huge social impact like rheumatoid arthritis are characterized by a chronic inflammatory state that is the main cause of damage and disability.
The transcription factors (TFs) of the NF-kB family are crucial regulators of acute and chronic inflammation, whose excessive activity is linked to tissue damage and survival of cancer cells. Drugs blocking NF-kB activation in a global manner are in clinical trials, but concerns about their safety have been raised because of the many physiological responses in which NF-kB is required. Conversely, therapies blocking the induction of subsets of NF-kB-regulated genes should provide restricted and predictable effects, but the molecular basis for their design are not available. The aim of this project is to identify and validate protein-protein interactions between NF-kB and transcriptional partners, which are required for target gene induction and amenable to small molecule-based perturbation.
We propose a rational combination of advanced technologies, including:
i) a genetic app roach to the identification of companion TFs and co-regulators required for induction of subsets of NF-kB target genes;
ii) in vivo analysis of co-occupancy of target genes by NF-kB and identified partners using chromatin immunoprecipitation;
iii) in vivo visualization of interactions using FRET on visible clusters of NF-kB-regulated genes;
iv) bioinformatics analysis and extraction of rules describing regulatory interactions.
The generation of a map linking protein-protein interactions to the induction of subsets of NF-kB-regulated genes will represent an essential tool in designing/screening drugs targeting NF-kB-dependent activities, and will provide new paradigms for "transcriptional therapies".
Call for proposal
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