CEREBROVASCULAR CONTRACTILE RESPONSES TO HIGH ALTITUDE LONG TERM HYPOXIA

高原长期缺氧的脑血管收缩反应

基本信息

批准号：
8704963
负责人：
LAWRENCE D LONGO
金额：
$ 22.03万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8704963
关键词：
Acclimatization Acute Address Adrenergic Agents Adrenergic Receptor Adult Agonist Altitude Altitude Sickness Animals Arteries Attenuated Biochemical Biogenic Amines Biological Assay Blood Vessels Blood flow Brain Brain Hypoxia-Ischemia Calcium Cardiovascular Diseases Cations Cell membrane Cells Cellular Retinol Binding Protein Cerebral Edema Cerebral Ischemia-Hypoxia Cerebral hemisphere hemorrhage Cerebrovascular Circulation Cerebrum Computer software Confocal Microscopy Coupling Data Analyses Dependence Development Disease Domestic Sheep Double-Stranded RNA Elements Endoplasmic Reticulum Enzymes Extracellular Signal Regulated Kinases FOS gene Fetus Filament Gel Gene Activation Gene Chips Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Transcription Genomics Growth and Development function Heart Diseases Hemorrhage Homeostasis Hypoxemia Hypoxia Image Infant Inositol Intraventricular Isoenzymes JUN gene Life Light Long-Term Effects Lung diseases MAPK1 gene Maintenance Maps Mass Spectrum Analysis Measures Mediating Messenger RNA Microfilaments Mitogen-Activated Protein Kinases Molecular Molecular Profiling Myosin ATPase Myosin Heavy Chains Neurologic Newborn Infant Nuclear Antigens Organism Pathway Analysis Pathway interactions Peptide Mapping Peptides Perfusion Perinatal subependymal hemorrhage Personal Satisfaction Phenotype Phenylephrine Phosphorylation Phosphotransferases Physiological Play Potassium Pre-Eclampsia Predisposition Protein Isoforms Protein Kinase C Proteins Proteomics Proto-Oncogenes Pulmonary Edema Pulmonary Hypertension Pump Qi RNA RNA Interference Regulation Research Retinol Binding Proteins Reverse Transcriptase Polymerase Chain Reaction Rho-associated kinase Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Sea Second Messenger Systems Secondary to Sheep Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Signaling Pathway Gene Signaling Protein Smoke Smooth Muscle Myocytes Smooth Muscle Myosins Solutions Staining method Stains Stimulus Stream Stress Testing Thick Transcript Transcription Factor AP-1 Up-Regulation Vascular Smooth Muscle Western Blotting Woman Work adrenergic age difference base caldesmon calponin cell growth cerebral artery cerebrovascular extracellular fetal inhibitor/antagonist insight mRNA Expression mature animal microchip multidisciplinary novel pregnant programs protein activation protein expression protein protein interaction receptor response rho second messenger virtual

项目摘要

The overall theme of this project is to understand whereby acclimatization to high altitude long-term hypoxia (LTH) alters fundamental mechanisms in the cerebrovasculature of the fetus and adult. We also will examine these mechanisms in association with development from fetus to adult. This project is broadly based, multidisciplinary, and vertically integrated using physiologic, cellular, biochemical, and molecular approaches. Based on two decades of research, we shall test a number of hypotheses in sheep acclimatized to high altitude. The overall hypothesis is that high altitude, long-term hypoxia is associated with changes in cerebrovascular contractile responses secondary to altered alphai-adrenergic-receptor (or AR) subtypes and/or specific protein kinase C isoforms (PKC)-mediated downstream Ca2+-dependent and Ca -independent signal transduction pathways. An associated hypothesis is that LTH significantly alters Oi-AR-subtype- and specific PKC isozyme-mediated expression of proto-oncogenes and genes representing vascular smooth muscle "synthetic" and/or "proliferative" phenotypes, as compared to those of adult "contractile" phenotype. Four specific aims will examine the role of LTH in cerebral artery Or adrenergic-mediated signal tranduction of thin and thick myofilament, e.g., 1) roles of Oi-AR, PKC isoforms, extracellular signal regulated kinases (ERKs), and downstream effector proteins, 2) the role of plasma membrane and sarcoplasmic reticulum Ca2+ channels, 3) gene regulation of vascular phenotypes, and 4) signaling pathways gene/protein discovery. For the studies we will utilize agonist-induced contractility and intracellular [Ca2+], Western immunobiots, RT-PCR, RNAi silencing, confocal microscopy, 2D-gel-mass spectroscopy, and gene microarray/pathways analysis. Scientifically the studies will augment our understanding of basic mechanisms whereby fetal and adult cerebral vessels acclimatize to LTH. They also will illustrate aspects of development from fetus to adult. Clinically the studies relate to at least three critical problems. 1) For the fetus and newborn they relate to responses to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are anemic, who have heart or lung disease; for the newborn altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) They also will contribute to understanding mechanisms of cardiovascular disorders and renatal "programming" of adult disease. 3) Finally, they are relevant to understanding mechanisms of diseases such as: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.

该项目的总体主题是了解，从而适应高海拔长期缺氧（LTH），改变了胎儿和成人脑桥梁的基本机制。我们还将研究这些机制，这些机制与从胎儿到成人的发展有关。该项目是基于生理，细胞，生化和分子方法的广泛基于多学科和垂直整合的。根据研究的二十年，我们将在适应高海拔的绵羊中检验许多假设。总体假设是，高海拔，长期缺氧与脑血管收缩反应的变化相关，继发于改变Alphai-肾上腺素能受体（或AR）亚型和/或特定蛋白质激酶C同工型（PKC） - 介导的下游CA2+依赖性依赖性 - 依赖于 - 依赖性 - 依赖性 - 依赖性 - 依赖性依赖性 - 和非依赖性信号转导途径。一个相关的假设是，LTH显着改变了原始基因基因和代表血管平滑肌“合成”和/或“增殖性”表型的原始基因和代表血管平滑肌“合成肌肉”和/或“增殖”表型的基因的oi-ar-ar-subtype-和特定的PKC介导的表达。 “表型。四个具体目标将检查LTH在脑动脉中的作用或肾上腺素介导的薄和厚肌丝的信号转移，例如1）OI-AR，PKC同工型的作用，细胞外信号调节激酶（ERKS）和下游效应蛋白，2）PLASMAMMEMBRANE和SARBBRANE和SARCOPLANS CAMBRANE CA2+ CAS2+通道，CA2+通道，s骨膜的作用3）血管表型的基因调节，以及4）信号通路基因/蛋白质发现。对于研究，我们将利用激动剂诱导的收缩力和细胞内[Ca2+]，西部免疫自变量，RT-PCR，RNAI沉默，共聚焦显微镜，2D-GEL-MASS光谱和基因微阵列/途径分析。从科学上讲，这些研究将增强我们对基本机制的理解，从而使胎儿和成人脑血管适应于LTH。他们还将说明从胎儿到成人的发展方面。临床上的研究与至少三个关键问题有关。 1）对于胎儿和新生儿，它们与居住在高海拔高度的女性以及吸烟或贫血的女性中，患有心脏或肺部疾病的妇女的反应有关；对于新生儿，用脑部出血和肺动脉高压改变了脑血管血流。 2）他们还将有助于理解成人疾病的心血管疾病和肾脏“编程”的机制。 3）最后，它们与理解诸如疾病的机制有关：急性山疾病，子痫前期和高海拔脑和肺水肿。