Contribution of IL6 trans signaling in older females after ischemic stroke

标题：IL6反式信号在老年女性缺血性卒中中的作用 摘要：女性在缺血性中风后的预后比男性更差。多种因素影响结果，包括性染色体组成(XX对XY)、性激素(雌激素对雄激素)和免疫反应。IL6是一种关键的炎性细胞因子，高水平的IL6与不良的卒中结局相关。IL6/IL6受体相互作用后的下游信号是通过JAK/STAT3途径介导的。这种信号级联对老年女性中风后的生物学影响尚不清楚。我们的长期目标是剖析缺血性卒中损伤后调节IL6/IL6R信号的性别依赖性分子机制，因为这一发现将促进老年女性的靶向治疗。这项建议的目的是确定小胶质细胞IL6R在卒中后长期功能结果中的作用，包括运动结果以及卒中后血管对认知障碍和痴呆(VCID)的贡献。中心假说是，IL6/IL6R信号在老年女性脑损伤的进展中起不利作用，而小胶质细胞IL6/IL6R信号功能障碍导致卒中后长期功能恢复不良。我们的特定目标将检验以下假设：老年女性中风后的过度炎症是IL6/IL6R反式信号增强的结果(目标1)；第二条X染色体有助于老年女性IL6/IL6R信号的增强(目标2)；老年雌性小鼠中的小胶质细胞IL6/IL6R的反式信号会加剧神经炎症和加剧中风后的功能缺陷，包括中风后的VCID(目标3)。完成后，我们将了解小胶质细胞IL6/IL6R信号对中风损伤后功能结果(包括认知功能下降)的性别依赖性作用。这一贡献意义重大，因为它将鼓励为老年中风患者开发性别依赖疗法的实验方法。我们还专注于探索认知功能随年龄增长的性别差异，因为众所周知，女性患痴呆症和阿尔茨海默病的风险更高。这项拟议的研究是创新的，因为我们将调查IL6R反式信号对老年女性卒中结局的贡献，这是迄今为止尚未探索的途径。对基于性的信号机制的洞察是至关重要的，因为它们可以被目前可用的治疗方法改变。

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.