ABSTRACT

Background: The immune system is the main pillar of the human body’s health. Accurate understanding of the immune modulators will enable us to precisely unveil the abilities of the immune system to fight virtually all human diseases. Chronic inflammation is the hallmark of many human pathologies including cancer and currently, anti-inflammatory therapy is focused on inhibiting production of eicosanoid mediators of inflammation (prostaglandings, thromboxanes, prostacyclins, leukotrienes) by inhibiting their producing enzymes (COX-1/2). Although efficient, recent discoveries emphasized potentially dangerous side effects of these drugs. Therefore, identification and validation of new molecules with anti-inflammatory potential and reduced side effects, becomes of major importance. In the recent years the development of molecules targeting signaling pathways involved in production and release of pro-inflammatory mediators, such as cytokines and chemokines, has gained field and forwards the concept of new-age therapies.
Hypothesis: Our hypothesis is that identifying small molecules, which target the production or secretion of pro-inflammatory cytokines from macrophages and monocytes, such as interleukin-1β (IL-1β), will provide an improved alternative for treating chronic inflammation associated with numerous pathologies.
Aim: This project aims to develop a sensitive high-throughput screening platform by generating an endogenously tagged interleukin-1β reporter cell line by CRISPR-Cas9 technology, able to monitor stimulated IL-1β secretion with the purpose to identify new chemical compounds with anti-inflammatory activity that will be validated in primary macrophages and a mouse model for sepsis.
Expected results: Implementation of this project will deliver a versatile screening platform for anti-inflammatory compounds and a list of validated small molecules with anti-inflammatory properties, which can be easily translated to pre-clinical studies.