Reversing Age Related Inflammation

逆转与年龄相关的炎症

• 批准号: 9906276
• 负责人: Louise D. McCullough
• 金额: $ 49.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906276
• 关键词: Age; Age-associated memory impairment; Aging; Animal Model; Animals; B-Lymphocytes; Behavior; Behavioral; Blood; Bone Marrow; Bone Marrow Transplantation; Brain; CCL11 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL10 gene; Cells; Chemotaxis; Chimera organism; Chronic; Clinical Research; Data; Delirium; Disease; Elderly; Elements; Flow Cytometry; Functional disorder; GDF11 gene; Goals; IL17 gene; Immune; Immune system; Immunity; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-17; Investigation; Ischemic Stroke; Knockout Mice; Lead; Leucocytic infiltrate; Link; Marrow; Mature Lymphocyte; Memory; Microglia; Modeling; Mus; Neuraxis; Neutrophil Infiltration; Parabiosis; Peripheral; Phenotype; Plasma; Plasma Exchange; Play; Prevalence; Proteomics; Recovery; Recovery of Function; Rejuvenation; Role; Serum; Stroke; T-Lymphocyte; Techniques; Therapeutic; Tissues; Transplantation; age effect; age related; aged; aging brain; body system; cohort; cytokine; disability; epidemiology study; experimental study; functional improvement; inflammatory milieu; ischemic injury; male; monocyte; mortality; neurogenesis; neutrophil; novel; post stroke; response; stroke outcome; stroke recovery; therapeutic target; transcriptome sequencing

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).

项目摘要 慢性低度炎症的全身性升高见于几乎所有外周器官系统， 衰老这种全身性的“炎症”对大脑功能有重大影响，使大脑容易受到 损伤这项提案的主要目标是调查和操纵慢性疾病的机制， 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，外周免疫攻击导致 中枢神经系统（CNS）的有害影响，如病态行为和谵妄。相反地， 尽管最近才认识到，原发性CNS损伤也可引发中枢神经系统的显著变化， 外围我们假设外周炎症的增加导致了高死亡率和不良预后。 老年动物中风后的功能恢复。手法逆转外周“炎症” 外周因子的增加将减少老年CNS中活化T细胞的数量， 激活，导致实验性中风后恢复增强。这一假设得到了最近 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式逆转： 从我们自己的数据中发现的年轻血液中发现的全身性因素的管理，显示了年轻血液的年轻化。 具有年轻骨髓的老年外周免疫系统降低死亡率并增强行为 中风后的康复 利用动物模型，我们将研究与年龄相关的细胞和体液变化之间的关系， 炎症和缺血性中风的结果，这将允许识别新的年龄适当的 治疗目标我们的初步数据表明，在老年小鼠中观察到的促炎表型 骨髓移植（BMT）可以逆转这种情况 一位年轻的捐赠者。我们将首先确定这种返老还童表型是否会导致长期的 中风后的功能改善骨髓移植对年龄相关中枢神经系统表型/功能的影响 然后将在从小鼠发育的嵌合体中检查常驻免疫细胞（CD 8 + T细胞和小胶质细胞 缺乏成熟的淋巴细胞。异时共生导致模型中类似的“返老还童”表型 与年龄相关的认知能力下降我们将联合收割机与蛋白质组筛选和RNA测序相结合 识别新型“促年轻”因素（Aim 2a）并研究这些因素如何与内在中枢神经系统相互作用 免疫细胞。最后，将研究血浆置换，以确定这些治疗益处是否可以被 在没有替换细胞成分的情况下重现（目的2b）。

项目成果

Microglia depletion increase brain injury after acute ischemic stroke in aged mice.

小鼠急性缺血性中风后，小胶质细胞耗竭会增加脑损伤。

• DOI: 10.1016/j.expneurol.2020.113530
• 发表时间: 2021-03
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Marino Lee S;Hudobenko J;McCullough LD;Chauhan A
• 通讯作者: Chauhan A

Old Maids: Aging and Its Impact on Microglia Function.

• DOI: 10.3390/ijms18040769
• 发表时间: 2017-04-05
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Koellhoffer EC;McCullough LD;Ritzel RM
• 通讯作者: Ritzel RM