The ability to recover from a stroke depends upon a balanced response ofthe immune system. In some cases, the immune system is unable to respond and negatively affects patient outcome. A simple and reliable biomarker to monitor the immune response to stroke is the ratio between the number of neutrophils and lymphocytes (NLR). This ratio is a prognostic biomarker for several cardiovascular risk factors and we have preliminary data suggesting high NLR can predict death and functional dependence following stroke. However, the mechanisms unifying the NLR with dysfunctional immune crosstalk following ischemic stroke are unknown. Neutrophils release Arginase 1 (ARGI) resulting in L-Arginine depletion and a dosedependent decrease in T lymphocyte proliferation. It is likely CVD severity contributes to dysregulated Immune crosstalk following ischemic stroke. The objective of this project is to explore the relationships beh/i/een CVD and ARGI with the NLR to discover the mechanisms behind dysregulated adaptive immune responses to inflammatory signals following ischemic stroke.We hypothesize that neutrophil mediated ARGI release contributes to T lymphocyte suppression following stroke, mediated by pre-morbld CVD.
Aims : 1. Determine the relationship between ARGI, the NLR and CVD severity in human ischemic stroke. 2. Determine the relationship between ARG1 and the NLR in obese and lean zucker rats (OZR &LZR) undergoing middle cerebral artery occlusion (MCAO). 3. Identify the functional relationship between neutrophil mediated ARGI T cell suppression in stroke. 4. Develop and implement a mentor training plan for Dr. Barr to acquire the experimental skills to address the specific needs of aim 2 and 3.
The aims i n this study are designed to uncover the variability in post-stroke immune suppression. This would aid in personalized secondary risk stratification (e.g. infection, cerebral edema, poor recovery) and treatment allocation following stroke. An additional expected outcome of this study is the identification of novel therapeutic targets for stroke treatment. Information obtained in this study can be used in the clinical setting to monitor risk for secondary stroke complications and stratlfiy treatment to those who are most likely to beneft.
Understanding the role of the immune in the contribution of cardiovascular disease in stroke as well as the mechanism by which immune dysfunction worsens stroke outcome is critical to the effective treatment of and recovery from stroke. The propose project would adress these important issues.