Cardiovascular diseases like atherosclerosis are one of the leading causes of death in developing nations. Various factors including diet, lifestyle, and genes have been attributed to the development of these diseases. One of the main mechanisms implicated in disease progression is the activation of the innate immune system, and the subsequent production of proinflammatory mediators, in particular by monocytes and macrophages. Studies have demonstrated that the proinflammatory cytokine, IL-1b is a key mediator during atherosclerosis and blocking IL-1b could be beneficial. The production of IL-1b requires the activation of multimeric protein complexes called inflammasomes that are triggered in response to a wide range of stimuli including pathogens and host derived danger signals, including cholesterol crystals. Activated inflammasomes produce functional Caspase-1 required for IL-1b production. However, the molecular mechanisms by which inflammasome activation is regulated and its implication to atherosclerosis are still poorly understood. In this project, I will focus on how ICEBERG modulates the activation of inflammasomes, particularly NLRP3, in the context of atherosclerosis. My central hypothesis for this proposal is that ICEBERG prevents the activation of the NLRP3 inflammasome in response to cholesterol crystals, fatty acids and high fat diet by binding to Caspase-1 and thereby, blocking the interaction of Caspase-1 with the adaptor molecule, ASC. In the first aim, I will investigate the mechanism by which ICEBERG interferes with the production of mature IL-1b in response to signals that contribute to atherosclerosis. I will utilize human and mouse macrophage cell lines and primary macrophages either expressing or lacking ICEBERG for these biochemical studies. In the second aim, I will utilize our novel monocyte/macrophage-lineage-specific ICEBERG transgenic mice, since ICEBERG is lacking from mice, to determine the role of ICEBERG in vivo during atherosclerosis by utilizing ApoE knockout mouse that expresses or lacks ICEBERG. This unique mouse model will enable me to study how macrophage specific expression of ICEBERG can ameliorate atherosclerosis. Upon completion of this project, I expect to provide mechanistic insights into inflammasome regulation by protein inhibitors such as ICEBERG during cardiovascular disease. Additionally, the results from this study may aid in the development of peptide inhibitors to block excessive inflammasome activation.
|Effective start/end date||7/1/15 → 6/30/17|
- American Heart Association Midwest Affiliate (15POST25690052)
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