Contribution of IL6 trans signaling in older females after ischemic stroke

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Title: Contribution of IL6 trans signaling in older females after ischemic stroke Abstract: Women have worse outcomes after ischemic stroke than men. Multiple factors influence the outcomes including sex chromosome complement (XX vs. XY), sex hormones (estrogens vs. androgens), and immune responses. IL6 is a key inflammatory cytokine, and higher levels of IL6 are associated with poor stroke outcomes. Downstream signaling after IL6/IL6 receptor interaction is mediated through the JAK/STAT3 pathway. The biological impact of this signaling cascade in aged females after stroke is unknown. Our long-term goal is to dissect sex-dependent molecular mechanisms that regulate IL6/IL6R signaling after ischemic stroke injury; as this discovery will facilitate targeted therapeutics in elderly females. The objective of this proposal is to determine the role of microglia IL6R in long-term functional outcomes after stroke, including for motor outcomes as well as for post-stroke vascular contributions to cognitive impairment and dementia (VCID). The central hypothesis is that IL6/IL6R signaling plays a detrimental role in the progression of cerebral injury in aged females, and dysfunctional microglia IL6/IL6R signaling contributes to poor long-term functional recovery after stroke. Our specific aims will test the following hypothesis: Exaggerated inflammation in aged females after stroke is a consequence of enhanced IL6/IL6R trans-signaling (Aim 1); the second X chromosome contributes to enhanced IL6/IL6R signaling in aged females (Aim 2); Microglia IL6/IL6R trans-signaling in older female mice heightens neuroinflammation and exacerbates functional deficits after stroke, include post-stroke VCID (Aim 3). Upon completion, we will understand the sex-dependent role of microglial IL6/IL6R signaling on functional outcomes after stroke injury, including cognitive decline. This contribution is significant since it will encourage experimental approaches to develop sex-dependent therapeutics for elderly stroke patients. We are also focused on exploring the sex differences in cognitive functions with age as it is well known that women are at higher risk for dementia and Alzheimer's disease. The proposed research is innovative because we will investigate the contribution of IL6R trans-signaling on stroke outcomes in older females, a heretofore unexplored avenue. Insights into sex-based signaling mechanisms are essential, as they can be modified by currently available therapy.