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Gender-Specific Treatment of Pediatric Cardiac Arrest

小儿心脏骤停的性别针对性治疗

基本信息

批准号：
7586596
负责人：
Robert S B Clark
金额：
$ 23.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586596
关键词：
Acetylcysteine Acute Address Adolescent Adult Affect Age Apoptosis Apoptosis Promoter Apoptotic Asphyxia Attenuated Behavioral Biochemical Brain Brain Injuries Brain Ischemia Cardiac Cardiopulmonary Arrest Caspase Caspase Inhibitor Cell Death Cessation of life Child Childhood Chronic Clinical Clinical Trials Clinical Trials Design Coma Complement Coupled Cysteine Data Disease Equilibrium Esters Etiology Evaluation Female Foundations Gender Glutamic Acid Glutathione Glutathione Metabolism Pathway Glycine Gonadal Steroid Hormones Guidelines Harvest Heart Arrest Heart failure Hippocampus (Brain)Human Hypoxemia Impairment In Vitro Infant Intervention Investigation Ischemia Knowledge Measures Mediating Metabolism Methods Modeling Molecular Morbidity - disease rate Motor Nerve Degeneration Neurologic Neurological outcome Neurons Organ Outcome Outcome Assessment Outcome Study Pathway interactions Patients Peroxonitrite Physiologic Monitoring Predisposition Principal Investigator Rattus Reduced Glutathione Reperfusion Therapy Research Proposals Resuscitation Rodent Sex Characteristics Sexual Maturation Short-Term Memory Signal Transduction Staurosporine Survivors Testing Therapeutic Therapeutic Effect Translating Treatment Efficacy United States United States National Institutes of Health age group boys caspase-2 clinically relevant cohort cytotoxicity design functional outcomes girls improved in vivo in vivo Model injured innovation male mortality natural hypothermia neonatal hypoxic-ischemic brain injury neuron loss neuronal survival neuroprotection nitrosative stress novel postnatal pre-clinical prevent programs rehabilitation strategy response sex tool

项目摘要

DESCRIPTION (provided by applicant): Cardiopulmonary arrest in infants and children remains a significant cause of morbidity and mortality. The principle factor influencing outcome in survivors of cardiopulmonary arrest is the neurologic sequelae resulting from hypoxic-ischemic encephalopathy, unfortunately, there are no interventions to reverse the cellular consequences of hypoxic-ischemic encephalopathy. A clinically relevant model of pediatric asphyxial cardiac arrest in postnatal day 17 rats has been developed that has the capacity for invasive physiologic monitoring and resuscitation that mimics guidelines used in humans, biochemical and cellular assessment, and acute and long-term functional outcome assessment with the potential for application of rehabilitation strategies. Preliminary data show key gender differences in glutathione metabolism and activation of apoptotic cascades in the injured brains of juvenile rats after asphyxia and neurons in culture, implying that pathways leading to neurodegeneration and ultimate cell death and survival may be different between sexes. This is of paramount importance because in the present day infants and children are treated similarly after cardiopulmonary arrest whether they are boys or girls, and both genders are affected by this clinical entity in similar proportions. To our knowledge the influence of gender in the pathobiology of hypoxic-ischemic encephalopathy after cardiopulmonary arrest prior to sexual maturation has not been thoroughly addressed. Using this in vivo model of asphyxial cardiopulmonary arrest in juvenile rats, coupled with parallel in vitro studies, the hypothesis that global hypoxemia-ischemia/reperfusion initiates gender specific cell death pathways and reversible neurological impairments will be tested. Specific Aims are designed to determine whether neuroprotection can be achieved using novel therapies specifically targeting glutathione depletion and apoptosis, and whether therapeutic efficacy is gender-dependent. Dismal outcomes seen in infants and children after cardiopulmonary arrest and the resultant societal impact warrant rigorous pre-clinical testing in a clinically relevant model. The primary objective of this research proposal is to identify efficacious and gender-specific the clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest and gender-specific, therapeutic strategies, to serve as the foundation for clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest.

描述（由申请人提供）：婴儿和儿童的心肺骤停仍然是发病和死亡的一个重要原因。影响心肺骤停幸存者预后的主要因素是缺氧缺血性脑病引起的神经系统后遗症，不幸的是，没有干预措施可以逆转缺氧缺血性脑病的细胞后果。已开发出出生后第 17 天的小儿窒息心脏骤停的临床相关模型，该模型具有模拟人类使用指南的侵入性生理监测和复苏、生化和细胞评估以及急性和长期功能结果评估的能力，并具有应用康复策略的潜力。初步数据显示，幼年大鼠窒息后受损大脑和培养神经元中谷胱甘肽代谢和细胞凋亡级联激活存在关键性别差异，这意味着导致神经变性和最终细胞死亡和存活的途径可能在性别之间有所不同。这是至关重要的，因为当今的婴儿和儿童在心肺骤停后无论是男孩还是女孩都会受到类似的治疗，而且两种性别都以相似的比例受到这种临床实体的影响。据我们所知，性别对性成熟前心肺骤停后缺氧缺血性脑病病理学的影响尚未得到彻底解决。使用幼年大鼠窒息心肺骤停的体内模型，结合平行的体外研究，将测试全身低氧血症-缺血/再灌注启动性别特异性细胞死亡途径和可逆神经损伤的假设。具体目标旨在确定是否可以使用专门针对谷胱甘肽耗竭和细胞凋亡的新疗法来实现神经保护，以及治疗效果是否具有性别依赖性。婴儿和儿童心肺骤停后的惨淡结果以及由此产生的社会影响需要在临床相关模型中进行严格的临床前测试。本研究提案的主要目的是确定旨在改善婴儿和儿童心肺骤停后结局的有效且针对性别的临床试验以及针对性别的治疗策略，作为旨在改善婴儿和儿童心肺骤停后结局的临床试验的基础。