Control of Neonatal Circulation

新生儿循环的控制

基本信息

批准号：
8675900
负责人：
CHARLES W. LEFFLER
金额：
$ 40.12万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-04-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675900
关键词：
Address Aftercare Agonist Antioxidants Asphyxia Asphyxia Neonatorum Astrocytes Attenuated Bilirubin Blood Circulation Blood Vessels Blood flow Brain Carbon Monoxide Cephalic Cerebrovascular Circulation Cerebrum Cessation of life Collection Coupling Data Depressed mood Detection Development Disease Endothelial Cells Excitatory Amino Acids Failure Family suidae Functional disorder Glutamates Healthcare Heme Human Hypoxia In Vitro Injury Intervention Intracranial Hemorrhages Investigation Ischemia Laser Scanning Confocal Microscopy Mass Fragmentography Measures Mediating Mediator of activation protein Mental Depression Microcirculation Modeling Morbidity - disease rate Muscle function Neonatal Neonatal Brain Injury Neurological outcome Newborn Infant Oxygenases Patch-Clamp Techniques Perinatal Perinatal Brain Injury Prevention Production Reactive Oxygen Species Regulation Reperfusion Therapy Research Ryanodine Receptors Seizures Signal Transduction Slice Smooth Muscle Smooth Muscle Myocytes Stimulus Survivors System Techniques Technology Testing Topical application Vascular Diseases Vasodilation arteriole cerebrovascular cost cytokine disability fetal heme oxygenase-1 heme oxygenase-2 improved in vivo inhibitor/antagonist injured mortality novel novel strategies prevent public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Investigation of mechanisms involved in perinatal asphyxia-induced cerebrovascular dysfunction is important because fetal and neonatal asphyxia can cause of perinatal brain damage and failure of blood flow regulation is a critical component. Carbon monoxide (CO) from astrocyte heme oxygenase (HO) is important in regulation of newborn cerebral circulation and preliminary data suggest HO products can provide cerebrovascular and astrocytic protection from asphyxia-induced damage. The research proposed pursues the unifying hypothesis that, in newborn brain, asphyxia disrupts astrocyte CO signaling and cerebral arteriolar smooth muscle (VSM) Ca2+ signaling and/or BKCa channel activity causing cerebrovascular dysfunction, while elevation of cytoprotective CO and bilirubin limit the dysfunction. To test this hypothesis, four specific hypotheses will be tested using a novel asphyxia model in newborn pigs: 1. Asphyxia injures astrocytes causing loss of CO-mediated dilation of pial arterioles, 2. Asphyxia depresses cerebral VSM CO-induced Ca2+ sparks, BKCa channel activity, and dilation, 3. Reactive oxygen species (ROS) are major contributors to asphyxia-induced astrocyte and VSM injury, and 4. Cytoprotective CO and bilirubin reduce asphyxia-induced ROS and post-asphyxia astrocyte and VSM dysfunction. Techniques will be used that allow investigation of intact newborn cerebral microcirculation in vivo, isolated pressurized cerebral arterioles, and freshly isolated astrocytes, microvessels and smooth muscle cells. Such research is unique by studying intact cerebral circulation, production of CO by intact brain and isolated astrocytes and microvessels, and investigating, at the cellular level, mechanisms responsible cerebral vascular dysfunction. In addition, experimental interventions that may attenuate cerebrovascular malfunction caused by asphyxia are examined. Cranial windows allow observation of microcirculation, collection of cortical CSF and topical application of agonists, precursors and inhibitors. CO production in vivo and in vitro is identified and quantified by gas chromatography-mass spectrometry. Astrocytes, cerebral arterioles, and cerebral arteriole smooth muscle cells isolated from control and post-asphyxia brains allow study of ROS, CO production, arteriolar reactivity, and vascular smooth muscle function. Global cytosolic Ca2+ and Ca2+ sparks in brain slices, intact arterioles and VSM will be studied using fluorescent indicator technology with a dual excitation, single emission system and laser scanning confocal microscopy, respectively. Patch clamp techniques will be used to examine BKCa channel activity. These studies are important because disorders of the cerebral circulation in the newborn period are major causes of sickness and death and can result in lifelong disabilities in survivors.

描述（由申请人提供）：研究围产期窒息引起的脑血管功能障碍的机制很重要，因为胎儿和新生儿窒息可能导致围产期脑脑损伤和血流调节的失败是关键成分。星形胶质细胞血红素氧酶（HO）的一氧化碳（CO）对于调节新生儿脑循环很重要，初步数据表明HO产品可以提供脑血管和星形胶质细胞保护，可免受窒息诱导的损害。这项研究提出了这样一个统一的假设，即在新生大脑中，窒息破坏了星形胶质细胞CO信号传导和脑小动脉平滑肌（VSM）CA2+信号传导和/或BKCA通道活动，从而导致脑血管功能障碍，同时甲状腺功能低下，同时升高甲状腺皮质co和biliririrubibin lim and bilirirubin limsfun。 To test this hypothesis, four specific hypotheses will be tested using a novel asphyxia model in newborn pigs: 1. Asphyxia injures astrocytes causing loss of CO-mediated dilation of pial arterioles, 2. Asphyxia depresses cerebral VSM CO-induced Ca2+ sparks, BKCa channel activity, and dilation, 3. Reactive oxygen species (ROS) are major contributors to窒息引起的星形胶质细胞和VSM损伤，以及4。细胞保护CO和胆红素可减少窒息诱导的ROS和敏感后星形胶质细胞和VSM功能障碍。将使用允许研究完整新生儿脑微循环的技术，在体内，分离的加压脑小动脉以及新鲜分离的星形胶质细胞，微血管和平滑肌细胞。通过研究完整的大脑循环，通过完整的大脑和孤立的星形胶质细胞和微丝生产CO，并在细胞水平上研究负责脑血管功能障碍的机制，这是独一无二的。此外，检查了可能减轻窒息引起的脑血管故障的实验干预措施。颅窗可以观察微循环，皮质CSF的收集以及激动剂，前体和抑制剂的局部应用。通过气相色谱 - 质谱法鉴定并量化了体内和体外的CO生产。星形胶质细胞，脑小动脉和大脑平滑肌细胞从对照和敏感后大脑中分离出来，可以研究ROS，CO产生，小动脉反应性和血管平滑肌功能。将使用具有双重激发，单发射系统和激光扫描共聚焦显微镜的荧光指示器技术研究脑切片，完整的小动脉和VSM中的全局胞质CA2+和Ca2+火花。斑块夹技术将用于检查BKCA通道活动。这些研究很重要，因为新生儿时期的脑循环疾病是疾病和死亡的主要原因，可能导致幸存者终生残疾。