CARBON MONOXIDE IN NEWBORN CEREBRAL CIRCULATION

新生儿大脑循环中的一氧化碳

基本信息

批准号：
7891977
负责人：
CHARLES W. LEFFLER
金额：
$ 5万
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：
1991
资助国家：
美国
起止时间：
1991-08-16 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7891977
关键词：
Address Adenylate Cyclase Affect Agonist Blood Vessels Brain Carbon Monoxide Catabolism Cells Cephalic Cerebrovascular Circulation Cerebrum Cities Collection Communication Cyclic AMP Cyclic GMP Data Detection Dilator Disease Doctor of Philosophy Endothelium Enzymes Face Family suidae Gases Heme Human Resources Hypoxia In Vitro Instruction Investigation Ion Channel Life Liquid substance Measurement Measures Mediator of activation protein Membrane Potentials Metabolism Microcirculation Modification Molecular Morbidity - disease rate Muscle Tonus Names Nature Neonatal Nerve Neuroglia Neurons Newborn Infant Oxygenases Phosphorylation Physiological Potassium Channel Primary Cell Cultures Principal Investigator Printing Probability Production Protein Isoforms Regulation Research Research Personnel Research Project Grants Rest Role Second Messenger Systems Site Smooth Muscle Soluble Guanylate Cyclase Survivors Techniques Tennessee Testing Tissues Topical application Translational Regulation Universities Vascular Endothelium Vascular Smooth Muscle Vasodilation base cerebrovascular design disability enzyme activity heme 1 heme a heme oxygenase-1 heme oxygenase-2 in vivo inhibitor/antagonist mortality programs protein expression response second messenger tool

项目摘要

The gas, carbon monoxide (CO), is produced physiologically by catabolism of heme via heme oxygenase. One of the isoforms of heme oxygenase, HO-2, is expressed in highest concentration in the brain where it resides in neurons, vascular endothelium and smooth muscle. It generates CO from cellular heme. This application is based on preliminary data that suggest carbon monoxide (CO) is an endogenous mediator in the newborn cerebral circulation. These preliminary data include detection of heme oxygenase 2 (HO-2) in the cerebral vasculature, cerebrovascular dilator responses to exogenously applied CO and to heme oxygenase substrate, and measurements of CO production by cerebral microvessels and endothelium. The likelihood that CO will prove to be a physiologically significant intercellular messenger molecule is high. The research proposed is designed to pursue the unifying hypothesis that CO is an integral component of microvascular control in neonatal cerebral circulation. To test this hypothesis, three specific aims will be addressed in newborn pigs, in vivo, and using cells isolated from newborn pigs, in primary culture: 1. Determine the functional significance of CO in regulation of cerebral microvascular tone, 2. Localize and characterize heme oxygenase of the neonatal cerebral vasculature, 3. Investigate mechanisms of CO induced modifications of cerebral microvascular tone. To accomplish these aims, techniques allowing investigation of intact cerebral microcirculation, isolated cerebral microvessels, and primary culture of cells from newborn pigs will be employed. Such research is unique by studying intact cerebral circulation and investigating, at the cellular and molecular levels, the mechanisms responsible for controlling the production of the mediator, CO, and the mechanisms by which CO can affect vascular tone. Cranial windows allow observation of cerebral circulation, collection of cortical periarachnoid fluid, and topical application of agonists, precursors and inhibitors. Levels and cellular distribution of heme oxygenase protein expression as well as enzyme activity and cellular mechanisms for controlling that activity will be examined. The cellular mechanisms by which CO may modify vascular tone will be studied at the level of membrane potential, ion channels, and second messengers. Disorders of the cerebral circulation in the newborn period are major causes of morbidity and mortality and can result in life long disabilities in survivors. Control of cerebrovascular circulation is easily impaired by pathological conditions. Therefore, better understanding of mechanisms of cerebromicrovascular humoral communication in newborns is needed badly. 3ERFORMANCE SITE(S) (organization, city, state) The University of Tennessee, Memphis Memphis, TN 38163 KEY PERSONNEL. See instructions on Page 11. Use continuationpages as neededto provide the required information in the format shown below. Name Organization Role on Project Charles W. Leffler, Ph.D. The University of Tennessee Principal Investigator Helena Parfenova, Ph.D. The University of Tennessee Co-Principal Investigator David Mendelowitz, Ph.D. The University of Tennessee Co-Investigator PHS 398 (Rev. 4/98) Page 2 BB Number pages consecutively at the bottom throughoutthe application. Do not use suffixes such as 3a, 3b. cc Princ fivestigator/Program Director (Last, first, middle): 5SW. Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (Fortype specifications, see instructions on page6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,

气体一氧化碳（CO）是通过血红素氧酶的血红素分解代谢在生理上产生的。中的一个血红素氧酶HO-2的同工型在其驻留在神经元中的大脑中以最高浓度表达血管内皮和平滑肌。它从细胞血红素产生CO。此应用程序基于提示一氧化碳（CO）的初步数据是新生儿脑循环中的内源介体。这些初步数据包括检测脑血管中的血红素加氧酶2（HO-2）扩张器对外源施用的CO和血红素加氧酶底物的反应，以及CO产生的测量值通过脑微血管和内皮。 CO被证明是生理意义的可能性细胞间信使分子很高。提出的研究旨在追求统一的假设是新生儿脑循环中微血管控制的组成部分。为了检验这一假设，三个在新生猪，体内和使用从新生猪分离的细胞中，将解决特定目的培养：1。确定CO在脑微血管调节调节中的功能意义，2。定位和表征新生儿脑脉管系统的血红素氧化酶，3。研究CO诱导的机制脑微血管张力的修饰。为了实现这些目标，技术允许调查完整脑微循环，孤立的脑微血管和新生猪细胞的原发性培养雇用。通过研究完整的脑循环和研究，在细胞和分子水平，负责控制调解人，CO的机制和机制 CO可以影响血管张力。颅窗可以观察大脑循环，收集皮质周期性液以及激动剂，前体和抑制剂的局部应用。水平和细胞分布血红素加氧酶蛋白表达以及酶活性和控制活性的细胞机制将被检查。 CO可以修改血管张力的细胞机制将在膜电位，离子通道和第二使者。新生儿时期大脑循环的疾病是发病率和死亡率的主要原因，可能导致幸存者长期残障。控制脑血管循环很容易受到病理状况的损害。因此，更好地理解迫切需要新生儿中脑血管体液交流的机制。 3人性地点（S）（组织，城市，州）田纳西大学孟菲斯大学孟菲斯，TN 38163 关键人员。请参阅第11页上的说明。使用所需的ContinuationPages以下面显示的格式提供所需的信息。姓名组织角色查尔斯·莱夫勒（Charles W. Leffler）博士田纳西大学首席研究员 Helena Parfenova博士田纳西大学联合首席调查员 David Mendelowitz博士田纳西大学共同研究员 PHS 398（Rev. 4/98）Page 2 BB 整个应用程序中的底部连续数字页面。请勿使用3a，3b之类的后缀。 CC Princ Fivestigator/Program总监（最后，第一，中）：5SW。在每个打印页面的顶部和每个延续页面的顶部键入主要调查员/计划总监的名称。（Fortype规格，请参阅第6页上的说明。）研究赠款目录页码面部第1页描述，