Friday, November 22, 2024
11/22/2024
Project Summary/Abstract Inflammation is an essential component of vertebrate immunity against invading pathogens, foreign insults, or abnormal physiologic conditions. Cellular death programs, meant to eliminate infected, insulted, or abnormal cells, constitute frontline mechanisms in innate inflammation. Release of immunogenic cellular materials from dying cells contributes to the initial stages of inflammation (also called acute inflammation). Even though this process is meant to be protective, the loss of vital cells from infected/affected organs often results in acute tissue injury. As infection/insult is mitigated, acute inflammation is resolved with onset of tissue repair processes. However, if insult/infection continues, acute inflammation is not resolved. The persistent inflammation continues to injure tissues and subsequently leads to fatal organ damage. This process manifests in systemic diseases such as sepsis. The challenge remains in understanding how fundamental drivers of inflammation contribute to protective versus injurious inflammation. This knowledge is essential to design targeted intervention strategies against damaging inflammation without impeding protective inflammation. In this proposal, we will characterize how cellular death programs contribute to both protective and injurious inflammation in immune and non-immune cells during bacterial infections. We recently show that cell death-associated proteins, apoptotic caspase (CASP)8, necroptotic receptor interacting protein kinase (RIPK)3- and CASP8-RIPK3-associating partner RIPK1 dictate endotoxemia, pulmonary inflammation and sepsis in mice. CASP8 and RIPK3 amplify injurious inflammation while RIPK1 plays a protective role. These observations highlight that different components of cell death signaling contribute differentially to pathogen-induced diseases. Based on this evidence the central hypothesis of this proposal is: Members of cellular death signaling dictate both beneficial and injurious inflammation during multi-organ injury and must be targeted accordingly for therapy. In the specific aims of this proposal, we will utilize human cells, murine genetics, knockdown/knockout strategies to characterize how cell death-associated proteins contribute during bacteria-induced inflammation. We will also test chemical and new biological suppressors of cell death as anti-inflammatory strategies in these settings. This proposal is transformative in its potential to identify novel signaling steps of inflammation as well as future therapy targets. This proposal also retains a primary focus on training undergraduate students in research with the aim of preparing next generation of immunology researchers.
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