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

基本信息

批准号：
8136006
负责人：
JOHN W CHEN
金额：
$ 37.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8136006
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

项目摘要

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）：中风的治疗仅限于一些认可的治疗选择，例如溶栓疗法，这些治疗方法必须在刚性短的时间范围内进行，从而导致许多患者排除。除了这个时间范围之外，还有更少的有效治疗选择。因此，扩展当前疗法并开发新的治疗方案将是非常可取的。众所周知，炎症会扩大缺血性脑损伤，并对预后产生不利影响。尽管抗炎疗法在实验模型中可以有效，但到目前为止，人类试验尚未显示出明显的好处。虽然差异可能是多因素的，但一种促成因子可能与使用广泛的抗炎剂的使用有关，而不是针对特定分子途径的更集中疗法，而酶和酶证明是有害的，同时保持炎症反应的有益作用。评估和实施新型抗炎疗法的核心障碍是缺乏一种无创手段来跟踪中风期间炎症的演变，以观察目标疗法在体内动物模型和人类中的影响。在中风病变中，发现了大量的脊髓过氧化物酶（MPO），这是一种由许多活化炎性细胞分泌的高度氧化和破坏性酶。我们已经表明，MR成像剂BIS-5HT-DTPA-GD（MPO-GD）高度敏感，对于检测MPO活性。我们发现MPO-GD成像可以报告并串行跟踪MPO活动，以获取以前仅在离体研究中获得的信息。 MPO-GD成像结果与梗塞体积和梗塞后的MPO活性良好相关，即使在闭塞后21天。在初步研究中，用MPO抑制剂治疗的野生型小鼠以及MPO缺乏小鼠的小鼠在第21天梗塞体积上显示出大幅下降。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，并且减少MPO活性将改善中风结果。该提案的总体目标是研究中风进化中MPO与炎症之间的关系，并开发治疗方案，通过调节MPO活性/表达以及与溶栓疗法结合使用，以限制炎症损害。具体目的是1）将MPO建立为中风炎症的成像生物标志物，2）评估MPO作为中风的治疗靶标，以及3）确定MPO抑制和溶栓治疗之间的协同治疗方案。拟议的研究将为使用MPO分子成像的使用提供一个平台，以对中风中炎症的基本病理学研究以及旨在改变炎症的新型治疗干预措施的影响。最终，该提案的结果将通过提供一种无创方法来评估中风期间的炎症状态，改善对动物和人类中新型抗炎疗法的评估，并为中风提供新的治疗靶点的评估，从而为中风患者带来受益的阶段。公共卫生相关性：由于MPO-GD高度稳定，无毒，并且可用于在广泛的临床上重要的炎症性疾病中对MPO活动进行成像，因此这些研究可能为MPO成像的应用提供基础，以用于对人类炎症的诊断评估和MPO抑制人类的诊断评估，并用于改善新型治疗干预措施，以改善STROKE中的新型治疗措施。