Determining the conserved molecular mechanisms contributing to inflammation during Sepsis

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Project Summary Worldwide it is estimated that over 6 million people die each year as a result of sepsis. There are few clinical treatment options for patients, therefore, it is critical to determine the molecular mechanisms that occur during sepsis in order to identity new targets for therapeutic intervention. Here we identify the long noncoding RNA, GAPLINC, as a conserved gene between human and mice that is highly expressed in macrophages. We show that GAPLINC knockouts are resistant to LPS induced septic shock. The overall aim of this proposal is to determine how GAPLINC contributes to the immune response that leads to septic shock. In Aim 1 we will utilize our genetic mouse models to expand on our initial findings and determine what impact knockout or overexpression of GAPLINC has in response to gram negative induced sepsis in vivo. In Aim 2 we will determine the molecular mechanisms utilized by GAPLINC to influence immune genes. We will identify the minimal region within GAPLINC required to impact gene expression. We will determine the complexes GAPLINC makes either with RNA or proteins to function and finally we will identify any structural features within GAPLINC that mediates these interactions. In Aim 3 we will determine if GAPLINC is functionally conserved in humans by studying its role in controlling immune genes in primary human monocyte derived macrophages. This project will enable us to better understand the complex mechanisms that are at play during bacterial induced sepsis. By focusing on GAPLINC we will identify a new layer of regulation during sepsis providing us with new avenues for future drug development.