Longitudinal Monitor of Microglia Activation After Stroke with SPION-enhanced MRI

使用 SPION 增强 MRI 纵向监测中风后小胶质细胞激活

• 批准号: 8871417
• 负责人: Yi Yang
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871417
• 关键词: Alzheimer' s Disease; Amyloid; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Basic Science; Biochemical; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Cells; Cerebral Ischemia; Cerebrum; Clinic; Clinical Research; Comorbidity; Confocal Microscopy; Contrast Media; Data; Detection; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Extravasation; Foundations; Goals; Growth; Growth Factor; Hematoxylin and Eosin Staining Method; Human; Image; Immune; Immunoglobulin G; Immunohistochemistry; Inbred SHR Rats; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Iron; Ischemia; Ischemic Stroke; Knowledge; Label; Lead; Lesion; Life; Location; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Medicine; Methods; Microglia; Middle Cerebral Artery Occlusion; Mission; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Patients; Pericytes; Peripheral; Permeability; Phase; Platinum; Play; Process; Proteins; Prussian blue; Public Health; Rattus; Reaction; Recovery; Recovery of Function; Reperfusion Therapy; Research; Rest; Role; Sensitivity and Specificity; Specificity; Staging; Staining method; Stains; Stroke; Techniques; Testing; Tight Junctions; Time; Tissues; Treatment Efficacy; Weight; antibody conjugate; blood perfusion; clinical practice; clinically relevant; cytokine; design; imaging biomarker; imaging modality; improved; in vivo; inflammatory marker; iron oxide; leukocyte activation; macrophage; nanoparticle; nervous system disorder; neuroinflammation; neurological recovery; neurorestoration; novel; novel therapeutics; public health relevance; repaired; research study; response; restoration; stroke recovery; therapeutic target; tissue regeneration; tissue repair

 DESCRIPTION (provided by applicant): Longitudinal monitoring of microglial activation after stroke with SPION-enhanced MRI ABSTRACT: Microglia are the brain-resident macrophages that form the first line of immunological defense in the brain. Emerging evidence indicates that microglial activation and leukocyte infiltration play a major role in the pathogenic cascades of cerebral ischemia: cellular reactions determine the extent of ischemia-induced tissue damage but are also necessary for tissue repair and regeneration during recovery. Despite the existence of a number of prior experimental and clinical studies focusing on activated microglia for the study of neuroinflammation after focal cerebral ischemia, an accurate, efficacious, and non-invasive method for monitoring the functional alteration of microglia during stroke recovery is stil lacking. Our preliminary results suggest that microglial activity is involved in the restoration of the integrity of the blood-brain barrier (BBB) during neurovascular remodeling after stroke at all stages, ranging from the early pro-inflammatory (M1) to the later anti-inflammatory and tissue repair (M2) stages. We propose to test the hypothesis that the functional alteration of microglia shifts from a classical early pro-inflammatory activation to the later expression of growth factors involved in neurovascular remodeling. In this proposal we will focus on applying a novel technique for MRI detection of microglial-targeted, superparamagnetic nanoparticles in rat brain to evaluate the alteration of microglia functional activation during stroke recovery. In this projet, we propose the following two specific aims; AIM1 to monitor the dynamic distribution profile of active microglia in rat ischemic brain with MRI and nanoparticles conjugated with a biomarker to microglia at 7, 14, and 28 days after stroke, and AIM2 to study the molecular and cellular changes during functional alterations of microglia in response to stroke-induced brain injury and recovery with histological and biochemical approaches. This proposal will combine the use of nanoparticles conjugated to an anti-Iba-1 antibody as a marker of microglia with MR imaging to non-invasively monitor the temporal profile of inflammation and microglia functional alteration in the brain after a stroke. Although the use of peripheral and imaging biomarkers have increased the specificity and sensitivity of the in vivo diagnosis of stroke, it would be of great clinical relevance to be able to non-invasively monitor the longitudinal development of inflammation in the brain of stroke subjects. MRI is widely used in medicine and widely available in clinical practice. Thus, an MRI method for imaging the inflammatory response inside the living stroked brain could be widely applied and would open these research areas to a great number of quantitative investigations in vivo where the efficacy of treatments could be determined and compared. This research will provide a novel experimental approach for monitoring the progression and treatment of stroke and other neurodegeneration disorders in support of direct subsequent applications in the clinic. In addition, the successful completion of the proposed studies will enhance our understanding of the functional alteration of microglia and the role of the key inflammatory events in neurovascular remodeling following stroke.

 描述(申请人提供)：用SPION增强MRI对中风后小胶质细胞激活的纵向监测摘要：小胶质细胞是驻留在大脑中的巨噬细胞，形成大脑免疫防御的第一道防线。新的证据表明，小胶质细胞的激活和白细胞的渗透在脑缺血的致病级联反应中起主要作用：细胞反应决定了缺血诱导的组织损伤的程度，但也是恢复过程中组织修复和再生所必需的。尽管已有大量以活化的小胶质细胞作为研究局部脑缺血后神经炎症的实验和临床研究，但仍缺乏一种准确、有效、非侵入性的方法来监测卒中恢复过程中小胶质细胞的功能变化。我们的初步结果表明，小胶质细胞的活动参与了小胶质细胞的修复 在卒中后神经血管重塑的所有阶段，从早期的促炎(M1)到后期的抗炎和组织修复(M2)，血脑屏障(BBB)的完整性。我们建议检验这样一种假设，即小胶质细胞的功能变化从经典的早期促炎激活转变为后来的生长因子表达。 参与神经血管重塑。在这项提案中，我们将重点应用一种新的MRI技术来检测大鼠脑内小胶质细胞靶向的超顺磁性纳米颗粒，以评估中风康复期间小胶质细胞功能激活的变化。在本项目中，我们提出了以下两个具体目标：AIM1用MRI和结合了小胶质细胞生物标记物的纳米颗粒动态监测大鼠脑缺血后7、14和28天小胶质细胞的动态分布；AIM2用组织学和生化方法研究卒中后脑损伤和恢复过程中小胶质细胞功能变化过程中的分子和细胞变化。这项建议将结合使用与抗Iba-1抗体连接的纳米颗粒作为小胶质细胞的标记与磁共振成像相结合，以非侵入性监测中风后大脑中炎症和小胶质细胞功能变化的时间分布。虽然外周和影像生物标志物的使用提高了卒中活体诊断的特异性和敏感性，但如果能够无创地监测卒中受试者脑部炎症的纵向发展，将具有重要的临床意义。磁共振成像在医学上有着广泛的应用，在临床上也得到了广泛的应用。因此，一种成像活体中风脑内炎症反应的MRI方法可以广泛应用，并将这些研究领域开放给体内的大量定量研究，从而可以确定和比较治疗的效果。这项研究将为监测中风和其他神经退行性疾病的进展和治疗提供一种新的实验方法，为后续的临床应用提供直接支持。此外，这些研究的成功完成将加深我们对小胶质细胞功能改变以及关键炎症事件在卒中后神经血管重塑中的作用的理解。