Wednesday, April 16, 2025
4/16/2025
Endothelial mechanisms of multiorgan dysfunction - PROJECT SUMMARY Three different fates await the millions of critically ill patients admitted to intensive care units every year. Close to 30% will recover without obvious sequelae, 15% succumb to the acute illness, and the remainder 55% will develop various degrees of long-term impairments in cognitive, immune, cardiovascular, or renal functions, leading to increased overall mortality. These sequelae are diagnosed under the umbrella term post-intensive care syndrome (PICS). We lack the knowledge to improve acute survival, and to predict and treat PICS. Largely, therapies for septic shock and other critially ill patients are limited to infectious source control and hemodynamic support. Severe systemic inflammatory reactions, including sepsis, often lead to shock, organ failure and death, in part through an acute release of cytokines that promote vascular dysfunction. The current body of work, including our own research, strongly argues for a critical role for the endothelium in determining the outcomes of critical illness through expression of multiple proteins to promote disseminated intravascular coagulopathy, leukostasis and edema. However, simply blocking cytokine activity does not improve survival, in large part due to the immunosuppresive actions of these treatments. It is imperative to rethink the problem. We posit that a better understanding of the endothelial mechanisms downstream of cytokine signaling will lead to improved therapies to prevent organ damage and mortality without interfering with the required pathogen clearance. Little is known about the endothelial signaling pathways regulating the transcriptional profile in failing organs. This proposal is designed to take full advantage of the innovative tools and knowledge we developed during the last several years to ask fundamental mechanistic questions on the role of endothelial signaling and transcriptional responses during severe inflammation. Sourcing of human primary endothelial cells in-house allows us to perform mechanistic studies in a cost-effective manner, a panel of endothelial-specific transgenic mice enables us to study key regulators of transcription in the context of multiorgan dysfunction, and clinical collaborators provide us with unique human specimens to ensure the translatability of our research. Our prior findings of a critical role for the IL6-STAT3-SOCS3 signaling axis in the endothelium provides a strong scientific basis for the proposed working model, and our new unpublished bioinformatics analysis of endothelial translatome of failing organs suggest several novel IL6 effectors of endotheliopathy, providing initial targets for further research. We aim at determining which changes dictate the severity of acute shock (and thus short-term survival), and which lead to long-term consequences well beyond the resolution of the initial shock. Key questions driving our research are: 1) What are the effectors downstream of a cytokine storm that we can target to limit organ dysfunction without limiting the immune response? 2) What are the main drivers of long-term consequences and chronic inflammation after shock recovery? 3) How can we take advantage of the complexity of the endothelial response to tailor it towards a pro-immune response while limiting the collateral damage? The outcome of our efforts in answering these critical questions is the discovery of key determinants of organ failure. The knowledge gained may lead to innovative non-immunosuppressive therapeutic strategies to limit organ dysfunction.
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