Serum amyloid A (SAA) proteins are critical to the regulation of inflammation in systemic as well as neurological diseases. Studies have shown that during an acute phase response (APR), SAA levels increase 1000-fold and can stimulate the inflammasome, trigger the recruitment of immune cells to inflammatory sites, and elicit the induction of enzymes that degrade extracellular matrix. Our long-term goal is to dissect the mechanisms regulating SAA function, particularly the contribution to stroke related damage. Recent studies have demonstrated that activation of the inflammasome is a critical event in stroke progression in mice. The central hypothesis is that SAA activates the NLRP3 inflammasome, and amplifying the local inflammatory responses that enhance neuronal cell death and stroke progression. Our specific aims will test the following hypotheses: Aim 1: Investigate the role of NLRP3 inflammasome in SAA's ability to exacerbate stroke in mice. Aim 1a. Using mice deficient in SAA, RAGE and various inflammasome components (cathepsin B, NLRP3, ASC, caspase-1 and IL-1beta) or IL-1R mice, we will determine whether SAA-mediated stroke outcomes are dependent on the NLRP3 inflammasome. Aim 1b. Using microglial cell cultures, we will determine the impact of SAA on RAGE mediated pathologies (ROS generation, etc.) as well as the influence of SAA-HDL on SAA-mediated NLRP3 activation. Aim 2: To test the hypothesis that systemic SAA exacerbates the progression of neuronal cell death and inflammation in stroke. Aim 2a. Using SAA deficient mice we will determine the impact on stroke infarct volume and outcomes. In addition, using viral vectors to express SAA as well as an inducible transgene will allow us to determine the role of SAA with specific expression of SAA. The impact of SAA on inflammation, neuronal cell death, matrix remodeling, etc. will be determined. Aim 2b. We will investigate the role of SAA and the inflammasome in human stroke, the relationship between plasma SAA, IL-1beta and the impact on stroke outcomes.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|