Examination of the therapeutic potential of TNK1 in prevention and healing of intestinal barrier breach

• Applicant: Milena Armacki, Ph.D.
• Subject Area: Gastroenterology ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459509442

microbiome; each element modifies the other via crosstalk with goal to preserve intestinal barrier and homeostasis. Disruption of symbiosis among these entities can lead to the local intestinal dysfunction but also systemic abnormalities such as bacterial translocation and sepsis that can culminate in multiple organ failure and fatality. We have shown that TNK1 kinase mediates intestinal barrier breach leading to septic shock and gut-origin induced MOF (Armacki, JCI, 2018). Disruption of intestinal homeostasis is also a hallmark of inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. TNK1 is upregulated also in these conditions while targeting of TNK1 in the gut protects the intestinal mucosa in the experimental model of colitis (Armacki, 2018). Thus, targeting of TNK to prevent or reduce intestinal barrier breakdown is a rational strategy to improve disease course. We aim here to investigate whether TNK-targeting strengthens the intestinal epithelial barrier and prevents increase in permeability in response to sepsis, improving disease course. To address this, we will examine genetic and pharmacologic targeting of TNK1 in experimental sepsis settings. Pharmacological targeting of the kinase by the use of small-molecule inhibitors holds great translational potential for clinical treatments of patients. Moreover, additional mechanistic studies are required to understand better how the fine-tuning of TNK1 expression can contribute to the maintenance of equilibrium between intestinal epithelium, microbiota and mucosal immune system. Therefore, we aim to explore interplay between gut microbiota and TNK1-expression signature. Understanding what in fact, decides on microbiome composition is the prerequisite for developing a microbiome-targeted therapy. Since targeting of a kinase that regulates normal and abnormal functions can have both favourable and unfavourable consequences, targeting of the downstream TNK1 targets can be a better strategy. Thus, we aim to identify and analyse single candidate genes and related pathways, differentially regulated in response to TNK1.

• DFG Programme: Research Grants