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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.

这个R21应用程序使用了高风险，高回报的细胞计数技术（缩写为CyTOF）