Aging and Innate immune system resilience in TBI

TBI 中的衰老和先天免疫系统恢复能力

• 批准号: 10369760
• 负责人: PAULA C BICKFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369760
• 关键词: Address; Adipose tissue; Age; Aging; Anti-Inflammatory Agents; Behavior; Biodistribution; Biological Process; Brain Injuries; Cell Separation; Cells; Chronic; Clinic; Data; Dementia; Dose; Effectiveness of Interventions; Elderly; Flow Cytometry; Goals; Hour; Human; Immune; Immune system; Immunohistochemistry; Immunologic Memory; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Innate Immune Response; Innate Immune System; Interleukin-6; Investigational Therapies; Ipsilateral; Knowledge; MALAT1 gene; Mass Spectrum Analysis; Measures; Memory impairment; Methods; Microglia; Modeling; Motor; Mus; Neurologic; Outcome; Pathology; Patients; Peripheral; Persons; Phagocytosis; Phenotype; Play; Population; Proteome; Proteomics; Publications; RNA; Regenerative Medicine; Reporting; Rodent; Role; Severities; Therapeutic; Therapeutic Intervention; Translating; Traumatic Brain Injury; Untranslated RNA; Vesicle; Vulnerable Populations; Work; aged; aging brain; aging population; cell motility; cell type; cognitive function; controlled cortical impact; exosome; high risk; immune function; improved; in vivo; inflammatory marker; military veteran; monocyte; nanoparticle; neurogenesis; novel; regeneration function; repaired; resilience; response; response to injury; stem cells; targeted treatment; tau Proteins; treatment optimization; treatment response

Traumatic brain injury (TBI) is a leading cause of neurological complications including chronic memory deficits such as dementia. Older TBI patients are at a higher risk for worsening of outcomes than their younger counterparts (Chou et al., 2018; Early et al., 2020; Morganti et al., 2016; Ritzel et al., 2019), despite the higher risk and worse outcomes, there are no targeted therapies targeted for this susceptible population, and only a few publications looking at therapeutics for this vulnerable population. This is compounded by data suggesting that older subjects may show less responsiveness to therapeutic interventions (Tajiri et al., 2014) which may indicate that aged individuals will require optimized treatments that differ from young. We have identified a therapy exosomes from human adipose derived stem cells (hASC exo) (Patel et al., 2018) that have a therapeutic window up to at least 48 hours post injury in young rodents (see preliminary data). The extended therapeutic window of hASC exo would be a major advancement over most current experimental therapeutics, with a treatment window of only hours and not days. To move this promising therapy forward we must address critical gaps in our knowledge regarding hASC exo’s mechanism of action, and effectiveness of the intervention in diverse age populations. Our hypothesis is that a major action of these hASC exosomes is to modulate the secondary immune response to injury by interacting with the immune system. It is already well established that in aged rodents aged there is an exaggerated response of innate immune cells to the injury. Our preliminary data demonstrates the efficacy of hASC exo to improve behavior and reduce inflammatory markers following CCI is modified in aged rodents . Thus, an unanswered question is how aging impacts the response to treatment, and specifically treatment with hASC exosomes.

创伤性脑损伤 (TBI) 是包括慢性记忆在内的神经系统并发症的主要原因 缺陷，例如痴呆症。老年 TBI 患者比年轻患者预后恶化的风险更高 同行（Chou et al., 2018; Early et al., 2020; Morganti et al., 2016; Ritzel et al., 2019），尽管更高 风险和更糟糕的结果，没有针对这一易感人群的靶向治疗，只有 很少有出版物关注这一弱势群体的治疗方法。数据表明这一点更加复杂 老年受试者对治疗干预的反应可能较差（Tajiri et al., 2014），这可能 表明老年人将需要与年轻人不同的优化治疗。我们已经确定了一个 来自人类脂肪干细胞 (hASC exo) 的治疗外泌体 (Patel et al., 2018) 幼年啮齿动物的治疗窗口期至少为受伤后 48 小时（参见初步数据）。扩展的 hASC exo 的治疗窗口将是大多数当前实验疗法的重大进步， 治疗窗口只有几小时而不是几天。为了推动这种有前景的疗法的发展，我们必须解决 我们对 hASC exo 的作用机制和有效性的认识存在重大差距 对不同年龄人群的干预。我们的假设是这些 hASC 外泌体的主要作用是 通过与免疫系统相互作用来调节对损伤的二次免疫反应。已经好了 确定在老年啮齿动物中，先天免疫细胞对损伤有过度反应。 我们的初步数据证明了 hASC exo 改善行为和减少炎症的功效 CCI 后的标记在老年啮齿类动物中发生了改变。因此，一个悬而未决的问题是衰老如何影响 对治疗的反应，特别是 hASC 外泌体治疗的反应。