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：
10301230
负责人：
HARRIS A GELBARD
金额：
$ 23.98万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301230
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 Fracture 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 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 repaired 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.

该 R21 应用程序使用高风险、高回报的质谱流式技术（缩写为 CyTOF）来识别介导中枢神经系统（CNS）神经炎症的免疫细胞亚群建立的术后谵妄（POD）骨科小鼠模型是免疫失调的标志。正常衰老；它也被认为是许多神经系统疾病的一个关键特征，包括痴呆症和谵妄等围手术期并发症很常见，高达 50% 的老年骨折后患者会出现这种情况。 POD 的最强危险因素是高龄和痴呆。谵妄的出现可能预示着痴呆症。事实上，谵妄叠加痴呆症（DSD）会导致痴呆。认知能力下降速度更快，死亡率也很高，这一点意义重大，因为有数百万人。每年定期接受骨科或其他手术的老年患者。衰老过程中 POD 和 DSD 的驱动力尚不清楚，并且没有批准的药物来治疗或预防它。开创了一种临床相关骨科手术小鼠模型，该模型显示全身炎症，改变在我们的模型中，手术动员了离散的免疫细胞。具有介导血脑屏障损伤的促炎信号反应的人群神经血管单位（NVU）并损害正常的突触转导，类似的免疫。具有相同促炎标记物的特征现已在精神错乱的液体生物标记物中得到描述然而，目前的免疫表型分析仅限于选定的非特异性细胞因子和亲细胞因子。脑组织（啮齿动物）和脑脊髓中的炎症分子，如 TNF、IL-1、IL-6、MCP-1 和 S100b 尚未有研究尝试公正地描述免疫子集对液体（人类）的特异性反应。我们提出两个具体目标：（1）定义年龄之间的差异。年轻成年（6mos）和老年（22mos）雄性和雌性小鼠调节中枢神经系统和中枢神经系统中的免疫细胞亚群骨科手术后的血液；(2) 使用以下方法确定阿尔茨海默病 (AD) 样病理特征的影响 5xFAD 6 个月大的转基因雄性和雌性小鼠（当 AD 和术后神经炎症骨科手术后中枢神经系统和血液中的免疫细胞亚群变得具有病理意义）。解析免疫细胞亚群并将其与促炎信号传导的离散序列相结合的能力 CyTOF 分子将是了解 POD 是否由神经炎症引起的关键这些实验将为外周迁移和/或中枢神经系统驻留免疫细胞奠定基础。未来的 RO1 研究中，我们将重点关注与以下疾病相关的 NVU 功能障碍的关键发现： NOT-AG-19-033 所寻求的阿尔茨海默氏病的神经退行性变，我们希望我们的研究结果能够有一个结果。对 ADRD 领域产生重要的积极影响，以减少老年人群中谵妄和痴呆症的影响帮助识别罹患 POD 和 DSD 风险较高的患者。