The Role of Pericytes in the Vascular Dysfunction of Sepsis

周细胞在脓毒症血管功能障碍中的作用

• 批准号: 10620403
• 负责人: Hongkuan Fan
• 金额: $ 37.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620403
• 关键词: Affect; Animal Model; Antisense Oligonucleotides; Apoptosis; Autopsy; Blood - brain barrier anatomy; Blood Vessels; Brain; CASP1 gene; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cytometry; Development; Encephalopathies; Exhibits; Extravasation; FLI1 Transcription Factor; FLI1 gene; Goals; Hippocampus; Image; Impaired cognition; Impaired health; Inflammation Mediators; Inflammatory; Knockout Mice; Laboratories; Memory impairment; Mental Health; Mus; Neuronal Dysfunction; Pathologic; Patients; Pericytes; Persons; Play; Production; Reporting; Research; Role; Sepsis; Survivors; Vascular Cognitive Impairment; Vascular Diseases; brain tissue; comparison control; improved; monocyte; neuroinflammation; neurovascular unit; novel; programs; recruit; response; septic patients; single nucleus RNA-sequencing; targeted treatment; treatment strategy

Project Summary: Sepsis affects more than 19 million people each year. With improved treatment strategies, more and more patients survive sepsis. The majority of these survivors develop cognitive impairment and mental health problems. However, the mechanisms that promote sepsis-associated encephalopathies (SAE) remain largely unknown, and there is a lack of SAE-targeted treatments. The long-term goals of our research program are to understand the mechanisms that lead to cerebrovascular dysfunction and cognitive impairment post sepsis and to develop novel targeted treatments for sepsis-induced cognitive impairment. To reach this goal, we characterized sepsis-induced cognitive impairment using animal models. We observed that mice exhibit hippocampus-dependent memory impairment associated with pathological neuron dysfunction. To understand the mechanisms behind cognitive impairment post sepsis, we focused on specialized cells in the brain called pericytes, which play a major role in regulating cerebral blood flow and maintaining blood brain barrier integrity. Pericytes form part of the neurovascular unit to meet the energy demands of the brain and facilitate neuro- inflammatory responses. However, the role of pericytes in sepsis-induced cognitive impairment remains unknown. Our studies demonstrated that the transcription factor friend leukemia virus integration 1 (Fli-1) regulates pericyte activation and viability. We also observed that brain pericyte numbers decreased after sepsis and that pericytes underwent apoptosis after their initial activation and production of inflammatory mediators. Pericyte loss resulted in vascular leakage and recruitment of inflammatory monocytes. We reported previously that Fli-1 governs pericyte viability through regulating caspase 1/3 expression. In our preliminary studies, we demonstrated that pericyte Fli-1 knockout mice exhibit decreased inflammatory mediator production in response to LPS. More importantly, we demonstrated that Fli-1 levels were higher in the hippocampus regions of post- mortem brain tissue from septic patients compared to controls. In this R35/MIRA application, we propose to use newly developed, unbiased approaches such as single nucleus RNA sequencing and imaging mass cytometry alongside inducible pericyte-specific Fli-1 knockout mice generated in our laboratory and novel antisense oligonucleotide Gapmers targeting Fli-1 recently developed by our group to understand the role of pericytes in vascular dysfunction and cognitive impairment post sepsis. The successful completion of the proposed studies will lead to better understanding of the mechanisms of vascular cognitive impairment post sepsis and the development of novel SAE-targeted treatments.

项目概要： 败血症每年影响超过1900万人。随着治疗策略的改进，越来越多的 患者在败血症中存活。这些幸存者中的大多数发展为认知障碍和心理健康 问题然而，促进脓毒症相关脑病（SAE）的机制在很大程度上仍然存在 未知，缺乏SAE靶向治疗。我们研究计划的长期目标是 了解脓毒症后导致脑血管功能障碍和认知障碍的机制， 为脓毒症引起的认知障碍开发新的靶向治疗方法。为了实现这一目标，我们 使用动物模型表征脓毒症诱导的认知障碍。我们观察到老鼠表现出 与病理性神经元功能障碍相关的海马依赖性记忆障碍了解 脓毒症后认知障碍的机制，我们专注于大脑中的特殊细胞， 周细胞，其在调节脑血流量和维持血脑屏障完整性中起主要作用。 周细胞形成神经血管单位的一部分，以满足大脑的能量需求，并促进神经元的生长。 炎症反应。然而，周细胞在脓毒症引起的认知障碍中的作用仍然存在， 未知我们的研究表明，转录因子朋友白血病病毒整合1（Fli-1） 调节周细胞活化和活力。我们还观察到脓毒症后脑周细胞数量减少 并且周细胞在其初始活化和产生炎症介质后经历凋亡。 周细胞损失导致血管渗漏和炎性单核细胞的募集。我们之前报道过 Fli-1通过调节caspase 1/3的表达来调控周细胞的活性。在初步研究中，我们 结果表明，周细胞Fli-1基因敲除小鼠在应答中表现出炎症介质产生减少， 到LPS。更重要的是，我们证明了Fli-1在海马区的水平更高， 与对照组相比，败血症患者的死亡脑组织。在此R35/MIRA应用中，我们建议使用 新开发的无偏倚方法，如单核RNA测序和成像质谱细胞术 与我们实验室产生的可诱导周细胞特异性Fli-1敲除小鼠和新的反义寡核苷酸一起， 我们小组最近开发了一种靶向Fli-1的寡核苷酸间隙聚体，以了解周细胞在 败血症后的血管功能障碍和认知障碍。成功完成拟议的研究 将有助于更好地了解脓毒症后血管性认知障碍的机制， 开发新型SAE靶向治疗。