Impact of Comorbidities on Stroke Outcomes and Treatments

补体系统在炎性损伤及其后续的发病机制中起重要作用 缺血性卒中后的康复。在前一个奖项中，我们确定了补体依赖机制 中风后的损伤和康复，我们鉴定了一组补体抑制剂，这些补体抑制剂的目标是 新表位在中风后受损的脑组织中表达。我们还确定了补体抑制 显著改善康复治疗和溶栓治疗这两个护理标准的结果。 这里提出的工作是这些机制和治疗研究的继续，但具有更深层次的 补体及补体抑制与t-PA及康复治疗相互作用的研究 (翻译上很重要)，虽然有两个主要的中风并存：老龄化和吸烟。香烟 吸烟(患者可改变的危险因素)和年龄与更高的死亡风险相关，更严重 中风患者的残疾、住院时间更长和整体功能恢复更差，年龄也是如此 与溶栓治疗反应较差有关。军事人员有明显更高的 吸烟的比例高于美国普通人群，而且在老年退伍军人和 患有创伤后应激障碍、成瘾和艾滋病毒等疾病的退伍军人。然而，尽管不断提出建议， 来自中风治疗学术行业圆桌会议(STAIR)委员会和资助机构的研究很少 已经解决了这些共病如何导致更糟糕结果的潜在机制。 在四个具体目标中，我们建议：1.确定年龄和吸烟对急性和慢性疾病的影响 卒中后补体依赖的神经炎症，并探讨补体调节在卒中后的作用 年龄和吸烟并存的设定；2.确定如何补充和修改 年龄和香烟烟雾暴露引起的神经炎性反应与现行标准相互作用 3.探讨补体抑制作为慢性阻塞性肺疾病的治疗策略 中风，以及补体在慢性损伤和修复中的作用；4.对于翻译关联性， 探讨全身性补体活性与血清IgM抗体水平及 合并疾病的急性卒中患者的卒中结局。

The complement system has an important role in the pathogenesis of inflammatory injury and subsequent recovery following ischemic stroke. In the previous award, we identified complement-dependent mechanisms of post-stroke injury and recovery, and we characterized a set of complement inhibitors that are targeted to neoepitopes expressed in the injured brain following stroke. We also determined that complement inhibition significantly improved the outcomes of rehabilitative therapy and thrombolytic therapy, two standards of care. The work proposed here is a continuation of these mechanistic and therapeutic studies, but with a deeper investigation into how complement and complement inhibition interacts with t-PA and rehabilitation therapy (translationally important), while layered on two major stroke comorbidities; ageing and smoking. Cigarette smoke (a patient modifiable risk factor) and age are associated with a higher risk of mortality, more severe disability, longer hospital stays and worse overall functional recovery in stroke patients, and age is also associated with a poorer response to thrombolytic therapy. Military personnel have a significantly higher rate of smoking than the general U.S. population, and it remains significantly higher among older age Veterans and Veterans with diseases such as PTSD, addiction, and HIV. However, despite continuous recommendations from the Stroke Treatment Academic Industry Roundtable (STAIR) committee and funding bodies, few studies have addressed the mechanisms underlying how these comorbidities contribute to worse outcomes. In four specific aims, we propose to: 1. Determine the effects of age and smoking on acute and chronic complement-dependent neuroinflammation after stroke, and investigate the effect of complement modulation in the setting of age and smoking co-morbidities; 2. Determine how complement and a modified neuroinflammatory response induced by age and cigarette smoke exposure interact with the current standards of care t-PA and rehabilitation therapy; 3. Investigate complement inhibition as a chronic treatment strategy for stroke, and the role of complement in both injury and repair chronically; 4. For translational relevance, investigate the correlation between systemic complement activity and serum levels of IgM antibodies and stroke outcomes in acute stroke patients with co-morbidities.