Immunoprofiling postoperative delirium during aging and neurodegeneration

衰老和神经变性期间术后谵妄的免疫分析

基本信息

批准号：
10456947
负责人：
HARRIS A GELBARD
金额：
$ 19.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456947
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia American Amyloid Animal Model Automobile Driving Bar Codes Biological Biological Assay Biological Markers Blood Blood - brain barrier anatomy Brain CCL2 gene Cells Cerebrospinal Fluid Cytometry Data Delirium Dementia Development Elderly Evolution Female Foundations Functional disorder Future Genetic Harvest Health Care Costs Human Human Amyloid Precursor Protein Immune Immune Targeting Immune response Immune signaling Immune system Immunity Immunophenotyping Impaired cognition Impairment Individual Inflammaging Inflammatory Inflammatory Response Interleukin-1 Interleukin-6 Isotopes Liquid substance Maps Mediating Memory impairment Metals Modeling Morbidity - disease rate Morphology Mus Nerve Degeneration Neuraxis Operative Surgical Procedures Orthopedic Surgery Orthopedics PTPRC gene Palladium Pathogenesis Pathologic Pathologic Processes Patients Perioperative complication Peripheral Phagocytosis Pharmaceutical Preparations Population Postoperative Period Procedures Public Health Quality of life Research Risk Risk Factors Rodent Role Sampling Signal Pathway Signal Transduction Signaling Molecule Stains Synapses TNF gene Techniques Testing Transgenic Organisms Trauma advanced dementia age difference aged aging population base bone fracture repair brain tissue chemokine clinically relevant cohort cytokine experience experimental study high dimensionality high reward high risk inflammatory marker insight male mortality mouse model mutant nervous system disorder neuroinflammation neurovascular injury neurovascular unit new therapeutic target normal aging older patient postoperative delirium presenilin-1 preservation prevent response sham surgery spatiotemporal systemic inflammatory response trafficking traumatic event validation studies young adult

项目摘要

This R21 application uses the high risk, high reward technique of mass cytometry (abbreviated as CyTOF) to identify immune cell subsets that mediate neuroinflammation in the central nervous system (CNS) in a well- established orthopedic mouse model of postoperative delirium (POD). Dysregulated immunity is a hallmark of normal aging; it is also recognized as a key feature of many neurological disorders including dementia and perioperative complications like delirium. POD is common, occurring in up to 50% of older patients after a fracture repair. The strongest risk factors for POD are advanced age and dementia. Interestingly, the postoperative emergence of delirium may presage dementia. In fact, delirium superimposed on dementia (DSD) contributes to a faster trajectory of cognitive decline as well as significant mortality. This is significant because of the millions of elderly patients that routinely undergo orthopedic or other surgeries every year. The biologic mechanisms that drive POD and DSD during aging are unknown and without approved drugs to treat or prevent it. We have pioneered a clinically-relevant orthopedic surgery murine model that displays systemic inflammation, alters microglial activation, and causes memory deficits in mice. In our model, surgery mobilizes discrete immune cell populations with pro-inflammatory signaling responses that mediate damage to the blood-brain barrier, damage the neurovascular unit (NVU) and impair normal synaptic transduction. Translationally, similar immune signatures with the same pro-inflammatory markers have now been described in fluid biomarkers of delirious patients. However, current immunophenotyping is limited to selected non-specific cytokines and pro- inflammatory molecules such as TNF, IL-1, IL-6, MCP-1 and S100b in brain tissue (rodents) and cerebrospinal fluid (humans). No study has yet attempted to unbiasedly profile the immune subset specific response to orthopedic surgical trauma in the CNS. We propose two specific aims: (1) to define how age differences between young adult (6mos) and elderly (22mos) male and female mice modulate immune cell subsets in the CNS and blood after orthopedic surgery; and (2) to determine the impact of Alzheimer’s (AD)-like pathologic features using 5xFAD transgenic male and female mice at 6mos of age (when AD and postoperative neuroinflammation become pathologically significant) on immune cell subsets in the CNS and blood after orthopedic surgery. The ability to resolve immune cell subsets and align them with discrete repertoires of pro-inflammatory signaling molecules with CyTOF will be key to understanding whether POD results from neuroinflammation due to peripherally migrating and/or CNS-resident immunocytes. These experiments will provide the foundation for future RO1 studies in which we pursue key findings focused on dysfunction of the NVU associated with neurodegeneration in Alzheimer’s disease as sought by NOT-AG-19-033. We expect our findings to have an important positive impact on the ADRD field to reduce the impact of delirium and dementia in the aging population by helping identify patients at greater risk for developing POD and DSD.

此R21应用使用高风险，高奖励技术的质量细胞仪（缩写为cytof）鉴定中枢神经系统（CNS）中介导神经炎症的免疫细胞亚群术后del妄（POD）建立的骨科小鼠模型。免疫失调是正常衰老；它也被认为是许多神经系统疾病的关键特征，包括痴呆和围手术期并发症，例如del妄。 POD很常见，发生骨折后多达50％的老年患者发生维修。 POD的强大风险因素是高龄和痴呆症。有趣的是，术后 ir妄的出现可能会预示痴呆症。实际上，在痴呆（DSD）上叠加的妄想有助于认知能力下降和重大死亡率的更快轨迹。这很重要，因为数百万每年常规接受骨科或其他手术的古老患者。生物学机制衰老期间的驱动豆荚和DSD尚不清楚，没有批准的药物来治疗或预防。我们有开创了与临床上相关的骨科手术鼠模型，该模型显示全身注射，改变小胶质激活，并导致小鼠的记忆防御。在我们的模型中，手术动员离散免疫细胞具有促炎性信号反应的种群，介导对血脑屏障的损害，损害神经血管单元（NVU）并损害正常的突触翻译。翻译，相似的免疫现在已经在Delirious的流体生物标志物中描述了具有相同促炎标记的签名患者。然而，当前的免疫表型限于选定的非特异性细胞因子和促进脑组织（啮齿动物）和脑脊髓中的TNF，IL-1，IL-6，MCP-1和S100B等炎症分子流体（人类）。尚无研究试图公正地介绍免疫子集的特定反应中枢神经系统中的骨科外科创伤。我们提出了两个具体目标：（1）定义年龄差异如何年轻成人（6mos）和较早的（22mos）雄性和雌性小鼠调节中枢神经系统中的免疫细胞亚群骨科手术后的血液；（2）确定使用阿尔茨海默氏症（AD）类似病理特征的影响 5XFAD转基因男性和雌性小鼠在6mos年龄（AD和术后神经炎症时）对中枢神经系统中的免疫细胞亚群和骨科手术后的血液中的免疫细胞亚群具有病理意义。这能够解决免疫细胞子集并与促炎信号的离散库对齐它们具有cytof的分子将是理解POD是否是由神经炎症引起的外围迁移和/或CNS居民免疫细胞。这些实验将为未来的RO1研究，我们购买的关键发现着重于与NVU相关的功能障碍 NOT-AG-19-033感知的阿尔茨海默氏病的神经变性。我们希望我们的发现有一个对Adrd领域的重要积极影响，以减少del妄和痴呆症对人口老龄化的影响通过帮助确定患有POD和DSD风险更大的患者。