Imaging and Treating Inflammation in Stroke by Targeting Myeloperoxidase

通过靶向髓过氧化物酶成像和治疗中风炎症

• 批准号: 8515539
• 负责人: JOHN W CHEN
• 金额: $ 36.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515539
• 关键词: Adverse effects; Affect; Alteplase; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Cells; Combined Modality Therapy; Diagnostic Imaging; Disease; Enzymes; Evaluation; Evolution; Exclusion; Experimental Animal Model; Experimental Models; Future; Gadolinium DTPA; Goals; Hour; Human; Image; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Ischemic Brain Injury; Lesion; Longitudinal Studies; Lovastatin; Magnetic Resonance Imaging; Maps; Methods; Microglia; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Patients; Peroxidases; Pharmaceutical Preparations; Regimen; Reporting; Saline; Serotonin; Staging; Stroke; Therapeutic; Thrombolytic Therapy; Time; Treatment Efficacy; Treatment Protocols; United States; Wild Type Mouse; Work; base; effective therapy; enzyme pathway; immunoregulation; improved; in vivo; inhibitor/antagonist; macrophage; molecular imaging; molecular/cellular imaging; monocyte; mortality; neutrophil; novel; novel therapeutic intervention; public health relevance; research study; spatial relationship; stroke therapy; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Treatment of stroke is limited to a few approved therapeutic options, such as thrombolytic therapy, that have to be administered within rigid short timeframes resulting in the exclusion of many patients. Beyond the this timeframe even fewer effective treatment options exist. Therefore, extending current therapies and developing new treatment options would be highly desirable. Inflammation has been known to extend ischemic brain injury and adversely affect outcome. Although anti-inflammatory therapies can be effective in experimental models, thus far human trials have not shown a clear benefit. While the discrepancy is likely multifactorial, one contributing factor may be related to the use of broad anti-inflammatory agents rather than more focused therapies that target specific molecular pathways and enzymes demonstrated to be deleterious while maintaining the beneficial effects of the inflammatory response. A central obstacle in evaluating and implementing novel anti-inflammatory therapies for stroke is the lack of a noninvasive means to track the evolution of inflammation during stroke to observe the impact of targeted therapies in in vivo animal models and humans. Myeloperoxidase (MPO), a highly oxidizing and damaging enzyme secreted by many activated inflammatory cells, is found abundantly in stroke lesions. We have shown that the MR imaging agent, bis-5HT- DTPA-Gd (MPO-Gd) is highly sensitive and specific for detecting MPO activity. We found that MPO-Gd imaging can report and serially track MPO activity to obtain information that was previously only available from ex vivo studies. MPO-Gd imaging results correlated well with infarct volume and detected MPO activity in the infarct even 21 days post occlusion. In preliminary studies, wild-type mice treated with an MPO inhibitor as well as MPO deficient mice demonstrated substantial decrease in day 21 infarct volume. Therefore, we hypothesize that secreted MPO is a key biomarker for inflammation and infarct propagation, and that reducing MPO activity would improve stroke outcome. The overall goals of this proposal are to study the relationship between MPO and inflammation in stroke evolution and to develop treatment regimens to limit the inflammatory damage by modulating MPO activity/expression and in combination with thrombolytic therapy. The specific aims are 1) to establish MPO as an imaging biomarker for inflammation in stroke, 2) to assess MPO as a treatment target for stroke, and 3) to determine synergistic treatment regimens between MPO inhibition and thrombolytic therapy. The proposed investigations will provide a platform for the use of MPO molecular imaging in future investigations of basic pathobiology of inflammation in stroke and the impact of novel therapeutic interventions aimed at altering inflammation. Ultimately, the results of this proposal will set the stage for translational projects to benefit stroke patients by providing a noninvasive method to assess the inflammatory status during stroke, improving assessment of novel anti-inflammatory therapies in animals and in humans, and offering a new treatment target for stroke. PUBLIC HEALTH RELEVANCE: Because MPO-Gd is highly stable, nontoxic, and can be used to image MPO activity in a a wide range of clinically important inflammatory diseases, these investigations may provide the basis for application of MPO imaging for diagnostic evaluation of inflammation in humans and MPO inhibition for novel therapeutic interventions to improve outcome in stroke and other diseases.

描述（由申请人提供）：中风的治疗仅限于少数已批准的治疗选择，例如溶栓治疗，这些治疗必须在严格的短时间内进行，导致许多患者被排除在外。超过这个时间范围，有效的治疗选择就更少了。因此，扩展现有疗法并开发新的治疗方案将是非常可取的。众所周知，炎症会延长缺血性脑损伤并对结果产生不利影响。尽管抗炎疗法在实验模型中可能有效，但迄今为止人体试验尚未显示出明显的益处。虽然这种差异可能是多因素造成的，但其中一个因素可能与使用广泛的抗炎药物有关，而不是针对特定分子途径和酶的更有针对性的治疗，这些药物被证明是有害的，同时保持了炎症反应的有益作用。评估和实施新型中风抗炎疗法的一个主要障碍是缺乏一种非侵入性手段来跟踪中风期间炎症的演变，以观察靶向治疗在体内动物模型和人类中的影响。髓过氧化物酶 (MPO) 是一种由许多活化的炎症细胞分泌的高度氧化和破坏性酶，在中风病变中大量存在。我们已经证明，MR 成像剂 bis-5HT-DTPA-Gd (MPO-Gd) 对于检测 MPO 活性具有高度敏感性和特异性。我们发现 MPO-Gd 成像可以报告并连续跟踪 MPO 活性，以获得以前只能从离体研究中获得的信息。 MPO-Gd 成像结果与梗塞体积密切相关，甚至在闭塞后 21 天也检测到梗塞中的 MPO 活性。在初步研究中，用 MPO 抑制剂治疗的野生型小鼠以及 MPO 缺陷小鼠在第 21 天的梗塞体积显着减少。因此，我们假设分泌的 MPO 是炎症和梗塞传播的关键生物标志物，并且降低 MPO 活性将改善中风结果。该提案的总体目标是研究中风演变过程中 MPO 与炎症之间的关系，并制定治疗方案，通过调节 MPO 活性/表达并与溶栓治疗相结合来限制炎症损伤。具体目标是 1) 建立 MPO 作为中风炎症的影像生物标志物，2) 评估 MPO 作为中风治疗靶点，3) 确定 MPO 抑制和溶栓治疗之间的协同治疗方案。拟议的研究将为 MPO 分子成像在未来研究中风炎症的基本病理学以及旨在改变炎症的新型治疗干预措施的影响中提供一个平台。最终，该提案的结果将为转化项目奠定基础，通过提供一种非侵入性方法来评估中风期间的炎症状态，改进对动物和人类新型抗炎疗法的评估，并为中风提供新的治疗靶点，造福中风患者。 公共健康相关性：由于 MPO-Gd 高度稳定、无毒，并且可用于对多种临床上重要的炎症性疾病中的 MPO 活性进行成像，因此这些研究可能为 MPO 成像应用于人类炎症的诊断评估和 MPO 抑制提供基础，以用于新的治疗干预措施，以改善中风和其他疾病的结果。