Aging and Innate immune system resilience in TBI

TBI 中的衰老和先天免疫系统恢复能力

基本信息

批准号：
10616497
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
项目类别：
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/10616497
关键词：
Address Age Aging Anti-Inflammatory Agents Behavior Biodistribution Biological Process Brain Injuries Cell Separation Cell secretion Cells Chronic Clinic Data Dementia Dose Effectiveness of Interventions Elderly Flow Cytometry Goals Hour Human 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 NF-kappa B Neurologic Outcome Pathology Peripheral Persons Phagocytosis Phenotype Play Population Predisposition Proteome Proteomics Publications RNA Regenerative Medicine Reporting Rodent Role Severities TBI Patients Therapeutic Therapeutic Intervention Translating Traumatic Brain Injury Untranslated RNA Vesicle Vulnerable Populations Work adipose derived stem cell aged aging brain aging population cell motility cell type cognitive function controlled cortical impact exosome high risk immune function immunoregulation improved in vivo inflammatory marker military veteran monocyte nanoparticle neurogenesis novel regeneration function repaired resilience response response to injury targeted treatment tau Proteins treatment optimization treatment response

Address Age Aging Anti-Inflammatory Agents Behavior Biodistribution Biological Process Brain Injuries Cell Separation Cell secretion Cells Chronic Clinic Data Dementia Dose Effectiveness of Interventions Elderly Flow Cytometry Goals Hour Human 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 NF-kappa B Neurologic Outcome Pathology Peripheral Persons Phagocytosis Phenotype Play Population Predisposition Proteome Proteomics Publications RNA Regenerative Medicine Reporting Rodent Role Severities TBI Patients Therapeutic Therapeutic Intervention Translating Traumatic Brain Injury Untranslated RNA Vesicle Vulnerable Populations Work adipose derived stem cell aged aging brain aging population cell motility cell type cognitive function controlled cortical impact exosome high risk immune function immunoregulation improved in vivo inflammatory marker military veteran monocyte nanoparticle neurogenesis novel regeneration function repaired resilience response response to injury targeted treatment tau Proteins treatment optimization treatment response

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项目摘要

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）是神经系统并发症的主要原因，包括慢性记忆痴呆等缺陷。年龄较大的TBI患者比年轻的患者更担心结果的风险同行（Chou等，2018; Farry等，2020; Morganti等，2016; Ritzel等，2019），Dospite较高。风险和较差的结果，没有针对这个易感人群的目标疗法，只有一个很少有出版物研究这种脆弱人群的治疗。这是由建议的数据加重的较老的受试者可能对治疗干预措施的反应较小（Tajiri等，2014），这可能表明老年人将需要与年轻人不同的优化治疗方法。我们已经确定了来自人脂肪衍生的干细胞（HASC EXO）的疗法外泌体（Patel等，2018）年轻啮齿动物受伤后至少48小时的治疗窗口（请参阅初步数据）。扩展 HASC EXO的治疗窗口将是大多数当前实验疗法的重大进步，只有几个小时而不是几天的治疗窗口。为了向前推进这种诺言疗法，我们必须解决我们关于HASC EXO的行动机制的重要差距和有效性干预潜水年龄的人群。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继发免疫反应。已经很好确定在老年啮齿动物中，先天性免疫细胞对损伤的反应夸大了。我们的初步数据证明了HASC EXO改善行为和减少炎症的效率 CCI后的标记在老年啮齿动物中被修饰。那是一个未解决的问题是衰老如何影响对治疗的反应，特别是用HASC外泌体治疗。