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Effect of Hemopexin Therapy after Intracerebral Hemorrhage

血红素结合蛋白治疗脑出血后的效果

基本信息

批准号：
8969426
负责人：
RAYMOND F REGAN
金额：
$ 23.4万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969426
关键词：
Accounting Affinity Anticoagulation Antihypertensive Agents Attenuated Autologous Behavioral Binding Binding Sites Blinded Blood Blood - brain barrier anatomy Blood coagulation Blood flow Brain Cell Survival Cells Cerebral hemisphere hemorrhage Clinical Trials Coagulation Process Corpus striatum structure Cytolysis Data Death Rate Disease Dose Edema Erythrocytes Female Free Radicals Future Gifts Glycoproteins Goals Hematoma Heme Hemin Hemoglobin Hemopexin Hemorrhage Hour Human In Vitro Infiltration Inflammatory Inflammatory Response Injection of therapeutic agent Injury Investigation Knockout Mice Knowledge Laboratories Lead Life Lipids Location Methemoglobin Modeling Morbidity - disease rate Mus Nervous System Trauma Neurons Outcome Outcome Measure Patients Plasma Plasma Proteins Play Population Process Proteins Publishing Randomized Reaction Reactive Oxygen Species Reporting Resolution Route Signal Transduction Stroke Structure Supportive care Therapeutic Time Tissues Toxic effect Toxin Translational Research Treatment Protocols Water base behavioral outcome cell injury central nervous system injury collagenase cost economic cost efficacy testing extracellular improved male milligram monocyte mortality neurotoxic neutrophil preclinical study prevent protective effect public health relevance research study statistics

项目摘要

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) accounts for 10-15% of strokes, and is associated with significant mortality, morbidity, and economic cost. Therapy is currently limited to hematoma evacuation when indicated, reversal of anticoagulation, antihypertensive therapy, and supportive care. The inadequacy of this approach is demonstrated by mortality statistics, which are unchanged over the past two decades. A growing body of experimental evidence suggests that toxins produced by the hematoma may contribute in delayed fashion to this poor outcome. One likely toxin is hemin, which is released from methemoglobin and is present in a hematoma in high micromolar concentrations. The primary defense against extracellular hemin is provided by hemopexin (Hx), a glycoprotein that binds it with extraordinary affinity and mitigates its pro-oxidant effect. Recent studies in the PIs laboratory have demonstrated that mice lacking Hx sustain more severe peri-hematomal injury and neurological deficits after ICH than their wild-type counterparts. However, no published studies have assessed the therapeutic potential of exogenous Hx therapy after ICH, likely due to its limited availability and prohibitive cost. The broad goal of this project, made feasible by n unrestricted gift of purified human Hx from CSL Behring, is to test the efficacy of Hx therapy in two established mouse ICH models. Preliminary experiments indicate that Hx has a robust protective effect on perihematomal cells when administered by i.p. injection after hemorrhage. Specific aims are as follows: 1) Induce striatal ICH by stereotactic collagenase or autologous blood injection in 4-6 month old male and female mice. Two or four hours later, randomly assign mice to treatment with purified human Hx or PBS vehicle control administered i.p. Quantify striatal cell viability, water and hemin content, hematoma size, inflammatory cell populations, blood-brain barrier integrity, perihematomal blood flow, and behavioral deficits 3 and 8 days later. 2) Guided by dose and time window results in younger mice, test efficacy of Hx therapy in 18-20 month old mice, quantifying the same outcome measures as in younger mice and also mortality rate. It is hoped that the results of this project will help to define the benefit of Hx therapy after ICH, and ultimately lead to clinical trials for a disease process that currently has few therapeutic options.