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Protective effect of astrocyte heme oxygenase-1 after intracerebral hemorrhage

星形胶质细胞血红素氧合酶1对脑出血后的保护作用

基本信息

批准号：
9914357
负责人：
RAYMOND F REGAN
金额：
$ 33.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-05 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914357
关键词：
Address Anticoagulation Antiinflammatory Effect Antioxidants Astrocytes Attenuated Behavioral Bilirubin Biliverdin reductase Biliverdine Blinded Blood Blood - brain barrier anatomy Blood Vessels Blood coagulation Blood flow Brain Brain hemorrhage Carbon Monoxide Cell Survival Cells Cerebral hemisphere hemorrhage Clinical Trials Cognitive Cognitive deficits Corpus striatum structure Cytolysis Death Rate Edema Enzymes Erythrocytes Event Excision Gene Transfer Generations Genetic Glial Fibrillary Acidic Protein Goals Hematoma Heme Hemin Hemoglobin Hemorrhage Histologic Hospital Mortality Hour In Vitro Inflammatory Inflammatory Response Injections Injury Iron Ischemic Stroke Knock-out Laboratories Lead Life Mediating Methods Modeling Morbidity - disease rate Mus Neuroglia Neurologic Deficit Neurological outcome Operative Surgical Procedures Outcome Oxygen Oxygenases Pathway interactions Pharmacotherapy Prevalence Protein Isoforms Quality of life Randomized Resistance Resolution Role Secondary to Series Serine Protease Stroke Sulforaphane Supportive care Survivors Systemic Therapy Therapeutic Thrombin Time Tissues Toxin Transgenic Mice Translational trial Ultrasonography United States base blood-brain barrier disruption cell injury collagenase design effective therapy experimental study heme oxygenase-1 heme oxygenase-2 hypertension control improved improved outcome in vivo mortality mutant novel outcome forecast overexpression oxidation photoacoustic imaging post stroke preconditioning protective effect

项目摘要

Project Summary/Abstract Intracerebral hemorrhage (ICH) is the primary event in about 10% of strokes, and has high morbidity and mortality rates. In addition to its mass effect, experimental evidence indicates that release of toxins such as hemoglobin from the hematoma contributes to cell loss in adjacent tissue. Cellular vulnerability to hemoglobin is largely a function of the activity of the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. HO activity has antioxidant and anti-inflammatory effects due to heme/hemin removal and generation of two breakdown products, biliverdin (converted to bilirubin by biliverdin reductase) and carbon monoxide. Prior studies have demonstrated that HO-1 overexpression by cultured astrocytes provides robust protection against heme-mediated injury, while HO-1 knockout is deleterious. In vivo, initial results indicate that transgenic mice overexpressing HO-1 in astrocytes sustain significantly less mortality and blood-brain barrier disruption after experimental ICH than their wild-type counterparts. Furthermore, systemic treatment with HO-1 inducers increases HO-1 in perivascular astrocytes and is also protective. The broad goal of this project is to further define the therapeutic potential of astrocyte HO-1 overexpression after ICH, using specific genetic methods for proof of concept followed by randomized blinded trials of translationally-relevant pharmacotherapies. Our experimental aims are as follows: 1) Produce striatal hematomas in wild-type (WT), GFAP-Cre-HMOX1fl/fl (astrocyte HO-1 KO), and GFAP.HMOX1 mice (astrocyte HO-1 overexpression) by stereotactic injection of blood or collagenase. Compare mortality, blood-brain barrier breakdown, striatal cell loss, inflammatory response, and behavioral/cognitive outcome. 2) Quantify perihematomal blood flow, oxygen saturation, and hematoma size in WT, GFAP-Cre-Hmox1fl/fl and GFAP.HMOX1 mice after ICH using micro ultrasound combined with photoacoustic imaging. Quantify blood vessels with unbiased histological analysis guided by design-based stereology. 3) Randomize GFAP-Cre- Hmox1fl/fl mice and Hmox1fl/fl controls to treatment with HO-1 inducers (sulforaphane, hemin) or vehicle, administered i.p. beginning 3 hours after striatal blood or collagenase injection. Quantify the effect on outcome as described above. It is hoped that completion of these aims will establish the benefit of astrocyte HO-1 overexpression after spontaneous ICH, and also demonstrate the feasibility of accomplishing this end with selected pharmacotherapies. This information will then provide the rational basis for clinical trials of novel agents for a stroke subtype that currently has few therapeutic options and a grim prognosis.

项目总结/文摘