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：
8011799
负责人：
LAWRENCE D LONGO
金额：
$ 20.91万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011799
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 Figs - dietary Filament Gel Gene Activation Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Transcription Genomics Growth and Development function Heart 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 Kinase 3 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 Up-Regulation Vascular Smooth Muscle Western Blotting Woman Work adrenergic age difference base caldesmon calponin cell growth cerebral artery cerebrovascular citrate carrier 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适应高海拔长期缺氧 (LTH) 是如何改变胎儿和成人脑血管系统的基本机制的。我们还将研究这些机制与从胎儿到成人发育的关系。该项目基础广泛、多学科、垂直整合，采用生理、细胞、生化和分子方法。基于二十年的研究，我们将在适应高海拔的绵羊身上检验一些假设。总体假设是，高海拔、长期缺氧与脑血管收缩反应的变化有关，继发于α1肾上腺素能受体（或AR）亚型和/或特定蛋白激酶C亚型（PKC）介导的下游Ca2+依赖性改变和Ca 独立的信号转导途径。一个相关的假设是，与成人“收缩性”相比，LTH 显着改变 Oi-AR 亚型和特定 PKC 同工酶介导的原癌基因和代表血管平滑肌“合成”和/或“增殖”表型的基因的表达。 ”表型。四个具体目标将检查 LTH 在脑动脉或肾上腺素介导的细肌丝和粗肌丝信号转导，例如 1) Oi-AR、PKC 同种型、细胞外信号调节激酶 (ERK) 和下游效应蛋白的作用，2) 质膜和肌浆网 Ca2+ 通道的作用， 3）血管表型的基因调控，4）信号通路基因/蛋白质发现。在这些研究中，我们将利用激动剂诱导的收缩性和细胞内 [Ca2+]、Western 免疫生物、RT-PCR、RNAi 沉默、共焦显微镜、2D 凝胶质谱和基因微阵列/通路分析。从科学角度来看，这些研究将增强我们对胎儿和成人脑血管适应 LTH 的基本机制的理解。他们还将说明从胎儿到成人发育的各个方面。临床上，这些研究至少涉及三个关键问题。 1) 对于胎儿和新生儿，它们与生活在高海拔地区的女性、吸烟或贫血、患有心脏病或肺病的女性对长期缺氧的反应有关；用于新生儿脑血管血流改变伴脑出血和肺动脉高压。 2) 它们还将有助于理解心血管疾病的机制和成人疾病的出生“编程”。 3) 最后，它们与理解疾病的机制有关，例如：急性高山病、先兆子痫、高原脑水肿和肺水肿。