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Endothelium-driven signaling network in the development of pulmonary hypertension

肺动脉高压发生过程中内皮驱动的信号网络

基本信息

批准号：
10247816
负责人：
Hua Linda Cai
金额：
$ 52.14万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247816
关键词：
Animal Disease Models Animals Arteries Attenuated Biological Availability Blood Vessels Candidate Disease Gene Cellular biology Collagen Coupling Data Deposition Development Dihydrofolate Reductase Disease Disease Progression Ear Electron Spin Resonance Spectroscopy Endothelial Cells Endothelium Enzymes Event GTP Cyclohydrolase I Gene Expression Profile Gene Expression Regulation Gene Transfer Techniques Genes Heart failure Human Hypertension Hypoxia Interruption Knock-out Knockout Mice Lesion LoxP-flanked allele Lung Medial Mediating Modeling Molecular Mus NADPH Oxidase NG-Nitroarginine Methyl Ester NOS3 gene Nitric Oxide Oxidation-Reduction Pathogenesis Pathologic Pathologic Processes Patients Phenotype Physiological Prevention Production Protein Isoforms Pulmonary Heart Disease Pulmonary Hypertension Pulmonary artery structure Pulmonology Rodent Role Signal Transduction Spectrophotometry Superoxides Systolic Pressure Therapeutic Thick Time Transgenic Mice Vascular remodeling Vascular resistance Ventricular attenuation cardiopulmonary system cofactor conditional knockout design efficacy evaluation endoplasmic reticulum stress endothelial dysfunction genetic strain human disease inhibitor/antagonist innovation mitochondrial dysfunction molecular phenotype mortality mouse model novel novel therapeutics overexpression preservation pressure prevent pulmonary arterial hypertension screening small molecule small molecule inhibitor tetrahydrobiopterin transcriptome sequencing translational study vasoconstriction

项目摘要

ABSTRACT ______ The central focus of application is to establish a novel pulmonary hypertension (PH) model in mice by specifically targeting the endothelium, and reveal a novel endothelium-driven signaling network of uncoupled eNOS-ER stress- mitochondrial dysfunction axis in the pathogenesis of PH, targeting of which would result in novel therapeutics for PH. Pulmonary hypertension is a severe human disease characterized by intensive remodeling of small arteries in the lung, resulting in vasoconstriction, elevated vascular resistance and pulmonary arterial pressure, and eventually right heart failure. In preliminary studies, we have generated a novel PH model by directly targeting eNOS to provoke eNOS uncoupling (DAHP to inhibit GTPCHI) and eNOS uncoupling-dependent endothelial dysfunction. Of note, endothelial dysfunction is one of the earliest events and may the initiating step of idiopathic pulmonary artery hypertension (IPAH). Importantly, DAHP-treated mice developed robust PH phenotypes of increased mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), accompanied by extensive vascular remodel characterized by typical human like vascular lesions of medial thickness, neointimal formation, and plexiform features. RNA-sequencing (RNA- seq) data indicated that, comparing to human patients with PH, the DAHP model had more overlappingly and substantially regulated genes vs. the hypoxia model (217 vs. 92). In preliminary studies we have also revealed new molecular mechanisms mediating PH development downstream of uncoupled eNOS, involving ER stress and mitochondrial dysfunction. Additionally, since reversal of eNOS cofactor tetrahydrobiopterin salvage enzyme dihydrofolate reductase (DHFR) deficiency downstream of NADPH oxidase (NOX) activation is robustly effective in preserving eNOS coupling activity, novel genetic strains specifically targeting NOX isoforms and DHFR will be examined for efficacies modulating PH phenotypes (16 novel and unique strains, most of which made in house). In Aim 1 we aim to establish a novel human like murine model of PH by fully characterizing phenotypes of DAHP-treated mice, and by comparing its gene regulation profile to that of human patients with PH and of Sugen5416/Hypoxia (SuHx)-treated mice. Also to further examine roles in PH development of novel candidate genes identified by RNA-seq analyses. In Aim 2, we will examine novel endothelium- driven signaling network of uncoupled eNOS-ER stress-mitochondrial dysfunction axis in the pathogenesis of PH using DAHP, hypoxia and Su/Hx models of PH. In Aim 3, we will examine whether strategies targeting endothelial DHFR, such as endothelium-specific transgenesis of DHFR, or knockout of NOX isoforms specifically in the endothelium to preserve DHFR function, would be of novel therapeutic potential for PH. We will also examine whether global and conditional knockout of DHFR, or endothelium-specific overexpression of NOX isoforms, leads to PH development and exaggerated PH. Effects on PH development of novel DHFR activators, and small molecule inhibitors for NOX, will also be examined. These studies are highly significant and translational in potentially identifying novel therapeutic options for the treatment and/or prevention of PH, namely via attenuation of NOX isoform activation to preserve endothelial DHFR function and eNOS coupling activity to shut down ER stress and mitochondrial dysfunction, or via direct activation of DHFR.

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