Human Cerebrospinal Fluid Macrophages and Outcome in Subarachnoid Hemorrhage

人脑脊液巨噬细胞和蛛网膜下腔出血的结果

• 批准号: 10372925
• 负责人: Khalid A. Hanafy
• 金额: $ 17.89万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372925
• 关键词: Admission activity; American; Aneurysmal Subarachnoid Hemorrhages; Apoptosis; Biological Assay; Biological Process; Blood Tests; Brain; Cell Line; Cells; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrum; Cessation of life; Clinical; Clinical Trials; Cognitive; Data; Detection; Disease; Erythrocytes; Flow Cytometry; Focal Neurologic Deficits; Functional disorder; Future; Hematoma; Heme; Hour; Human; Immune; Immunohistochemistry; Impaired cognition; Individual; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Magnetic Resonance Imaging; Measures; Microglia; Monitor; Morbidity - disease rate; Mus; Neurologic; Neuronal Injury; Neurons; Organ; Outcome; Pathology; Patients; Phagocytosis; Play; Publishing; Research; Resolution; Risk Factors; Role; Subarachnoid Hemorrhage; Time; Tissues; Translations; Triage; Vasospasm; X-Ray Computed Tomography; base; bench to bedside; clinical examination; cytokine; disability; heme a; high risk; individual patient; macrophage; mortality; mouse model; neuron apoptosis; new therapeutic target; novel; personalized approach; prevent; prospective; targeted treatment; virtual

The focus of research in aneurysmal subarachnoid hemorrhage for the last 30 years has been on understanding the pathophysiology of vasospasm and attempts to ameliorate it. Unfortunately, even when vasospasm is effectively treated, there is no improvement in death or disability. Subsequently, a novel concept and more effective endpoint for clinical trials emerged over the last 10 years: delayed cerebral ischemia (DCI), referring to new infarctions causing focal neurological deficits. Studies have shown that the occurrence of DCI is independently associated with morbidity, at least. The causes of DCI remains uncertain, but we believe that a focus on the cerebral inflammatory response (CIR) to the persistent heme burden that remains is a likely culprit for the initiation of DCI. While many independent associations for DCI exist, none account for the CIR in any way. Perhaps a focus on expedited hematoma resolution as well as finding some measure of the CIR to increase accuracy of DCI prediction is in order. Based on our mouse model of SAH, we found that the tissue resident macrophages of the brain are responsible for the majority of the CIR as well as for hematoma resolution. In our proposal, we use each individual patient’s cerebrospinal fluid (CSF) macrophages that are of tissue resident origin to study DCI and hematoma resolution. Specifically, we put these special macrophages in contact with a human neuronal cell line as a way to predict whether or not a patient might have DCI. We use flow cytometry to determine if the macrophages in the CSF are phagocytosing significant amounts of red blood cells to determine if the hematoma will resolve faster, and if this results in less DCI. We believe that these studies could provide a personalized approach to predicting DCI and hematoma resolution based on an individual’s innate immune profile. If validated in a prospective trial, these cell-based assays could be used to empirically discover new therapeutic targets for agents that could enhance RBC phagocytosis and reduce neuronal apoptosis by CSF macrophages, in an example of “bedside to bench” reverse translation.

过去30年来动脉瘤性蛛网膜下腔出血的研究重点是 了解血管痉挛的病理生理学并试图改善它。 不幸的是，即使有效治疗血管痉挛，死亡也没有改善 残疾。随后，出现了一个新颖的概念和更有效的终点 在过去的十年中：延迟的大脑缺血（DCI），指引起的新梗塞 局灶性神经缺陷。研究表明，DCI的出现是独立的 至少与发病率有关。 DCI的原因仍然不确定，但我们认为 专注于脑炎症反应（CIR）对持续的血红素伯嫩的关注 可能是DCI倡议的罪魁祸首。尽管存在许多DCI的独立关联，但 没有任何方式对CIR进行解释。也许关注加快血肿的分辨率 正如发现对CIR提高DCI预测准确性的一些测量。 基于我们的SAH小鼠模型，我们发现组织居民巨噬细胞的巨噬细胞 负责大多数CIR以及血肿的分辨率。在我们的提议中 我们使用每个患者的脑脊液（CSF）巨噬细胞 研究DCI和血肿分辨率的居民起源。具体来说，我们把这些特别 与人类神经元细胞系接触的巨噬细胞是一种预测是否是否 患者可能患有DCI。我们使用流式细胞术来确定CSF中的巨噬细胞是否为 吞噬大量的红细胞，以确定血肿是否会解决 更快，如果这导致DCI较少。 我们认为，这些研究可以为预测DCI和 基于个人先天免疫特征的血肿分辨率。如果在 前瞻性试验，这些基于细胞的测定可用于凭经验发现新的疗法 可以增强RBC吞噬作用并减少神经元细胞凋亡的靶标 CSF巨噬细胞，以“床头到长凳”的反向翻译为例。

项目成果

Microglial TLR4 is Critical for Neuronal Injury and Cognitive Dysfunction in Subarachnoid Hemorrhage.

• DOI: 10.1007/s12028-022-01552-w
• 发表时间: 2022-12
• 期刊: Neurocritical care
• 影响因子: 3.5

Quantitative susceptibility mapping improves cerebral microbleed detection relative to susceptibility-weighted images.

相对于磁敏度加权图像，定量磁敏图可改善脑微出血检测。

• DOI: 10.1111/jon.13054
• 发表时间: 2023
• 期刊: Journal of neuroimaging : official journal of the American Society of Neuroimaging
• 作者: Lee,Kyuwon;Ellison,Brian;Selim,Magdy;Long,NgoH;Filippidis,Aristotelis;Thomas,AjithJ;Spincemaille,Pascal;Wang,Yi;Soman,Salil
• 通讯作者: Soman,Salil

Gender differences in Alzheimer's may be associated with TLR4-LYN expression in damage associated microglia and neuronal phagocytosis.

• DOI: 10.1002/jcp.30916
• 发表时间: 2022-11
• 期刊: Journal of Cellular Physiology
• 影响因子: 5.6
• 作者: R. Islam;Robin Rajan;Hadi Choudhary;F. Vrionis;Khalid A. Hanafy

Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease.

• DOI: 10.3389/fimmu.2024.1332776
• 发表时间: 2024
• 期刊: Frontiers in immunology
• 影响因子: 7.3