Neutrophil-driven inflammation leads to carcinogenesis in IBD

Project: Research project

Description

Description: Inflammatory Bowel Disease (IBD) is a symptomatic disease where immune cell-mediated flares of inflammation cause severe and repeated intestinal tissue damage. Immune cells that arrive first to sites of tissue damage are called neutrophils. While neutrophils play key roles in host defense against invading pathogens, their dysregulated accumulation in the intestinal tissue results in severe injury to the epithelial cells that line the intestinal tract. Importantly, recurring neutrophil-mediated inflammation and injury to the colon in patients with IBD manifests itself as a symptomatic disease, and promotes tissue transformation and the development of colon cancer. Indeed, IBD patents are at a significantly higher risk of developing colorectal cancer (CRC), and the risk of cancer increases with the duration and severity of the disease.
There are a number of factors that maintain normal tissue function, and when disrupted lead to impaired healing and initiation of tumor development. For example, the nuclear envelope proteins called lamins, safeguard nuclear architecture, and regulate DNA replication and repair. Our exciting and novel preliminary findings, suggesting that during inflammation, tissue-infiltrating neutrophils release microparticles containing active molecules that target DNA repair proteins to inhibit DNA repair. This leads to accumulation of DNA damage, which can promote tissue injury and cellular transformation to cancer. Thus, neutrophils by causing recurring intestinal injury, as seen in IBD, can promote mutagenesis and inactivation of key tumor suppressor genes, facilitating the transition from IBD to CRC. Therefore the goal of this proposal is to define specific mechanisms and identify new biomarkers linking inflammation and cancer and aid in the development of new/improved therapies and diagnostic tools, aimed at protecting the general population and particularly, patients with IBD against CRC.
Our approach: In Aim 1 we will determine whether specific inhibition of neutrophil activity in the inflamed colon tissue is a feasible strategy to improve colonic healing and prevent IBD progression to CRC. In Aim 2 we will investigate the mechanisms by which neutrophils promote survival of epithelial cells with instable genomes (increased mutations). In aim 3 we will determine whether neutrophils promote inactivation the key tumor suppressor gene TP53 (this gene is the most frequently mutated gene, in IBD-associated CRC), thus promoting cellular transformation and cancer.
The proposed studies will use IBD and IBD-associated CRC human tissue, complemented by murine models of IBD and CRC and innovative genomic and molecular approaches. This project perfectly aligns with the CCFA mission to find the causes and cures for IBD. It aims to define new molecular targets that can help early diagnose cancer risk in patients with IBD and identify targets for more specific therapy (alternative to the generalized immunosuppression treatment for IBD used today) to protect the general population and particularly IBD patients against CRC.
StatusActive
Effective start/end date7/1/196/30/22

Funding

  • Crohn's and Colitis Foundation of America (Agmt 7/3/19)

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Inflammatory Bowel Diseases
Carcinogenesis
Neutrophils
Inflammation
Colorectal Neoplasms
DNA Repair
Wounds and Injuries
Neoplasms
Tumor Suppressor Genes
Colon
Epithelial Cells
Lamins
Patents
Immune System Diseases
p53 Genes
Nuclear Envelope
Complementary Therapies
Nuclear Proteins
DNA Replication
Early Detection of Cancer