Reversing Age Related Inflammation

项目摘要 慢性、低级别炎症的全身性升高见于几乎所有的外周器官系统 衰老。这种全身性“炎症”对大脑功能有重大影响，并使大脑容易受到 受伤。这项建议的主要目标是调查和操纵慢性阻塞性肺疾病的机制 炎症影响对缺血性中风的反应，缺血性中风是老年人长期残疾的主要原因。 实验、临床和流行病学研究表明，外周免疫挑战会导致 对中枢神经系统(CNS)的有害影响，如疾病、行为和精神错乱。相反， 尽管认识到的时间要晚得多，但初级中枢神经系统的侮辱也可以在 外围设备。我们假设外周炎症增加是导致高死亡率和低死亡率的原因。 老年动物中风后的功能恢复。运用手法逆转外周“炎症” 外周因素会减少老年中枢神经系统中活化的T细胞的数量，并减少小胶质细胞 激活，可促进实验性中风后的恢复。这一假说得到了最近几年 研究表明，与年龄相关的神经发生和记忆缺陷可以通过以下方法逆转 在年轻血液和我们自己的数据中发现的系统性因素的管理，显示出 衰老的外周免疫系统与年轻的骨髓一起降低死亡率并提高行为能力 中风后的康复。 通过动物模型，我们将研究细胞和体液中与年龄相关的变化之间的关系 炎症和缺血性卒中的结果，这将允许确定新的适合年龄的 治疗靶点。我们的初步数据表明，在老年小鼠中看到的促炎表型 导致较差的中风预后，这可以通过骨髓移植(BMT)来逆转 来自一位年轻的捐赠者。我们将首先确定这种返老还童的表型是否会带来持久的 卒中后功能改善。骨髓移植对增龄相关中枢神经系统表型/功能的影响 常驻免疫细胞(CD8+T细胞和小胶质细胞)随后将在小鼠发育的嵌合体中进行检测 缺乏成熟的淋巴细胞。在模型中，异慢性异种共生导致相似的“返老还童”表型 与年龄相关的认知功能减退。我们将把这项技术与蛋白质组筛选和RNA测序相结合 识别新的“促年轻化”因子(目标2a)，并研究这些因子如何与固有的中枢神经系统相互作用。 免疫细胞。最后，将对血浆交换进行研究，以确定这些治疗益处是否可以 扼要说明，但不替换细胞要素(目标2b)。

Project Summary Systemic elevation in chronic, low grade inflammation is seen across almost all peripheral organ systems with aging. This systemic “inflammaging” has a major impact on brain function and leaves the brain vulnerable to injury. The main goal of this proposal is to investigate and manipulate the mechanisms by which chronic inflammation impacts the response to ischemic stroke, the leading cause of long-term disability in the elderly. Experimental, clinical, and epidemiological studies demonstrate that peripheral immune challenges lead to detrimental effects in the central nervous system (CNS) such as sickness behavior and delirium. Conversely, although much more recently recognized, a primary CNS insult can also trigger dramatic changes in the periphery. We hypothesize that increased peripheral inflammation contributes to the high mortality and poor functional recovery seen after stroke in aged animals. Reversing peripheral “inflammaging” by manipulation of peripheral factors will decrease the number of activated T cells found in the aged CNS and reduce microglia activation, leading to enhanced recovery after experimental stroke. This hypothesis is supported by recent studies demonstrating that age-related deficits in neurogenesis and memory can be reversed by administration of systemic factors found in young blood and from our own data that shows rejuvenation of the aged peripheral immune system with young bone marrow reduces mortality and enhances behavioral recovery after stroke. Using animal models, we will examine the relationship between age-related changes in cellular and humoral inflammation and ischemic stroke outcome, which will allow for the identification of novel age-appropriate therapeutic targets. Our preliminary data suggests the pro-inflammatory phenotype seen in aged mice contributes to poor stroke outcome, and that this can be reversed by bone marrow transplantation (BMT) from a young donor. We will first determine whether this rejuvenation phenotype leads to long-lasting functional improvements after stroke. The effects of BMT on the phenotype/function of age-related CNS resident immune cells (CD8+ T cells and microglia) will be then examined in chimeras developed from mice lacking mature lymphocytes. Heterochronic parabiosis results in a similar “rejuvenation” phenotype in models of age-related cognitive decline. We will combine this technique with proteomic screens and RNA sequencing to identify novel “pro-rejuvenation” factors (Aim 2a) and investigate how these interact with intrinsic CNS immune cells. Finally plasma exchange will be investigated to determine if these therapeutic benefits can be recapitulated without replacement of cellular elements (Aim 2b).