Project Details
Projekt
Therapeutic targeting A20 for individualized therapy to improve the long-term outcome in alcohol-intoxicated trauma
Applicant
Professorin Dr. Borna Relja
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 465409392
Background: Severe trauma induces a systemic inflammatory response syndrome (SIRS), leading to excessive cytokine release (TNF-α, IL-1β, IL-6) and activation of immune cells. While inflammation is necessary for tissue repair, excessive activation can cause multi-organ dysfunction syndrome. Trauma patients often experience a biphasic immune response, transitioning from hyper-inflammation to compensatory anti-inflammatory response syndrome, increasing infection risk. Nuclear factor kappa B (NF-κB) plays a key role in trauma-induced inflammation, with the regulatory protein A20 (TNFAIP3) suppressing NF-κB and mitigating inflammation. However, its role in multi-organ trauma remains unclear. Acute alcohol intoxication (AAI) affects immune responses in a dual-phase manner: initially suppressing inflammation but later prolonging immune suppression, increasing infection risks and organ damage. This study investigates how AAI modulates A20 expression, impacting long-term trauma outcomes. Objectives: Building on preliminary data, this project aims to fine-tune immune responses post-trauma using TNIP3 inhibition, a specific A20 modulator. The project will test three hypothesis: H1: Increased A20 activity exacerbates immune suppression and long-term organ damage in trauma and AAI, H2: Targeting A20 via TNIP3 inhibition restores immune cell functions in primary cells from alcohol-intoxicated trauma patients, and H3: TNIP3 inhibition recalibrates inflammation, reduces organ damage, and improves long-term survival in mice after trauma and AAI. Methodology: The study comprises three interlinked work packages (WP1-3). WP1 - In vivo studies: Using A20 knockout (KO) and wild-type (WT) mice subjected to trauma and AAI, immune and organ responses will be assessed over 21 days. Key markers (TNF-α, IL-6, NF-κB activation, survival rates, and histological damage) will be measured. WP2 - Ex vivo immune function analysis: Blood samples from trauma patients will be analyzed for immune suppression markers, and TNIP3 inhibition will be tested in primary immune cells and hepatic cell lines to assess its ability to restore immune function. WP3 - Therapeutic targeting of A20: TNIP3 inhibition will be evaluated in vivo to determine its effect on inflammation, immune suppression, and long-term organ function with survival. Expected Impact: This study aims to identify A20 as a key regulator of post-trauma immune responses and evaluate TNIP3 inhibition as a potential therapy. Findings will provide insights into trauma-induced immune dysregulation and offer novel strategies to improve outcomes for alcohol-intoxicated trauma patients through precision immunomodulation.
DFG Programme
Research Units
