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,

这种气体，即一氧化碳 (CO)，是由血红素通过血红素加氧酶分解代谢而产生的。中的一个血红素加氧酶同工型 HO-2 在大脑中的神经元中表达浓度最高，血管内皮和平滑肌。它从细胞血红素产生二氧化碳。该应用程序基于初步数据表明一氧化碳 (CO) 是新生儿脑循环中的内源性介质。这些初步数据包括脑血管系统中血红素加氧酶 2 (HO-2) 的检测、脑血管扩张器对外源施加的 CO 和血红素加氧酶底物的反应，以及 CO 产生的测量由脑微血管和内皮细胞。 CO 被证明具有生理意义的可能性细胞间信使分子含量高。所提出的研究旨在追求一个统一的假设：CO 是新生儿脑循环微血管控制的重要组成部分。为了检验这个假设，三个将在新生猪体内解决具体目标，并使用从新生猪中分离的细胞进行初级研究培养： 1. 确定 CO 在调节脑微血管张力中的功能意义，2. 定位和表征新生儿脑血管系统的血红素加氧酶，3. 研究 CO 诱导的机制脑微血管张力的改变。为了实现这些目标，需要使用允许调查完整的技术脑微循环、分离的脑微血管以及新生猪细胞的原代培养受雇。此类研究的独特之处在于研究完整的脑循环并研究细胞和分子水平，负责控制介体、CO 产生的机制以及机制 CO 可以影响血管张力。颅窗可以观察脑循环、收集皮质蛛网膜周围液，以及局部应用激动剂、前体和抑制剂。的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该活性的细胞机制将接受检查。 CO 改变血管张力的细胞机制将在以下水平进行研究：膜电位、离子通道和第二信使。新生儿期脑循环障碍是发病率和死亡率的主要原因，并可能导致幸存者终身残疾。控制脑血管循环很容易因病理状况而受损。因此，更好地了解迫切需要新生儿脑微血管体液通讯的机制。 3ERFORMANCE SITE(S)（组织、城市、州）田纳西大学孟菲斯分校孟菲斯, 田纳西州 38163 关键人员。请参阅第 11 页上的说明。根据需要使用续页以如下所示的格式提供所需信息。名称组织在项目中的角色查尔斯·莱弗勒博士田纳西大学首席研究员海伦娜·帕尔费诺娃博士田纳西大学联合首席研究员大卫·门德洛维茨博士田纳西大学联合研究员 PHS 398（修订版 4/98）第 2 页 BB 在整个申请的底部连续编号页码。请勿使用 3a、3b 等后缀。 cc Princ Fivestigator/项目总监（最后、第一、中间）：5SW。在每个打印页和每个续页的顶部键入主要研究者/项目主管的姓名。（型号规格请参见第 6 页上的说明。）研究资助目录页码正面第 1 页描述，