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AMP Kinase regulation in persistent pulmonary hypertension of the newborn

新生儿持续性肺动脉高压中的 AMP 激酶调节

基本信息

批准号：
10210285
负责人：
GIRIJA G. KONDURI
金额：
$ 38万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210285
关键词：
5&apos -AMP-activated protein kinase ANGPT1 gene Affect Agonist Angiopoietin-2 Autopsy Biogenesis Birth Blood capillaries Blood flow Cell Proliferation Cells Cellular Metabolic Process Citric Acid Cycle Data Disease Ductus Arteriosus Endothelial Cells Endothelium Equilibrium FOXO3A gene Failure Fetal Sheep Gases Gene Expression Genes Genetic Transcription Glycolysis Hypoxemia Hypoxia Hypoxia Inducible Factor Impairment Infant Knockout Mice Knowledge Lead Life Ligands Link Lung Measures Metabolic Mitochondria Mus Newborn Infant Oxidative Phosphorylation Permeability Persistent Fetal Circulation Syndrome Phenotype Pulmonary Circulation Pulmonary Vascular Resistance Regulation Research Project Grants Respiratory Failure Role STK11 gene Signal Transduction Survivors Testing Therapeutic Agents Vasodilation Vasodilator Agents adenylate kinase angiogenesis base cell motility cofactor conditional knockout constriction density disability fetal hypoxia inducible factor 1 in vivo jagged1 protein knock-down lamb model lung development migration mortality risk novel novel therapeutics postnatal prenatal pressure pulmonary artery endothelial cell pulmonary function response sensor therapeutic evaluation therapy development transcription factor

项目摘要

Project Summary Persistent pulmonary hypertension of the newborn (PPHN) is a life threatening condition which results from failure of pulmonary vascular resistance to decrease at birth. The affected infants are hypoxemic and have an increased risk of death or long-term impairments for survivors. Recent studies identified 2 key alterations in PPHN lungs: (1) a decrease in mitochondrial biogenesis and oxidative phosphorylation in the pulmonary artery endothelial cells (PAEC) and (2) a decrease in angiogenesis, which contributes to failure of postnatal adaptation of pulmonary circulation. The overall objective of this research project is to identify mechanisms that underlie these 2 key alterations in PPHN. Preliminary studies conducted for this project identified decreased expression of liver kinase B1 (LKB1), a key upstream regulator of the energy sensor, 5’AMP activated protein kinase (AMPK) in PPHN. This alteration contributes to decreased expression of PGC-1α, a transcription cofactor required for mitochondrial biogenesis. Consistent with these changes, mitochondrial biogenesis is decreased in PPHN. In contrast, levels of hypoxia sensor, HIF-1α are increased in PPHN endothelial cells, leading to increase in glycolysis. The PAEC in PPHN show a switch in phenotype to predominantly tip cells from proliferative stalk cells. Whether the altered LKB1-PGC-1α signaling contributes to this phenotype switch is unknown. Studies proposed in this application investigate the hypothesis that decreased LKB1-PGC-1α signaling impairs mitochondrial biogenesis in PAEC and the resulting switch to glycolysis alters the PAEC phenotype specification to impair angiogenesis during a critical window of lung development. The hypothesis will be tested by 2 specific aims: (1) Investigate the role of decreased LKB1-PGC-1α signaling in the impaired mitochondrial biogenesis and increased HIF-1 α levels in PPHN and (2) Investigate the role of decreased LKB1-PGC-1α signaling in the PAEC phenotype switch and impaired angiogenesis in PPHN. The proposed studies will be done in fetal lambs with PPHN induced by prenatal constriction of ductus arteriosus, a known mechanism of PPHN. Completion of these studies will delineate the mechanism of increased pulmonary vascular resistance in PPHN. These studies will also provide the scientific rationale for testing therapeutic agents to increase LKB1 - PGC-1α signaling and cell permeable metabolic intermediates to restore angiogenesis in PPHN.

项目摘要新生儿持续性肺动脉高压（PPHN）是一种危及生命的疾病，出生时肺血管阻力未能降低。受影响的婴儿是低氧血症，增加幸存者死亡或长期损伤的风险。最近的研究确定了两个关键的改变， PPHN肺：（1）肺动脉线粒体生物合成和氧化磷酸化减少（2）血管生成减少，这有助于出生后的失败，适应肺循环。本研究项目的总体目标是确定 PPHN中这两个关键改变的基础。为该项目进行的初步研究发现，肝激酶B1（LKB 1）的表达，LKB 1是能量传感器的关键上游调节因子，5 'AMP活化蛋白 PPHN中的AMPK。这种改变导致PGC-1α（一种转录物）的表达减少线粒体生物合成所需的辅助因子。与这些变化相一致的是，线粒体的生物合成是 PPHN减少。相反，缺氧传感器HIF-1α在PPHN内皮细胞中的水平增加，导致糖酵解增加。PPHN中的PAEC表现为以尖端细胞为主的表型转换增殖的茎细胞。改变的LKB 1-PGC-1α信号传导是否有助于这种表型转换不明本申请中提出的研究调查了LKB 1-PGC-1α降低的假设，信号传导损害了PAEC中的线粒体生物合成，并且由此导致的糖酵解转换改变了PAEC 表型特异性在肺发育的关键窗口期间损害血管生成。的假设将通过两个具体目标进行测试：（1）研究LKB 1-PGC-1α信号转导在受损的 PPHN中线粒体生物合成和HIF-1 α水平升高的作用;（2）研究PPHN中线粒体生物合成和HIF-1 α水平降低的作用。 LKB 1-PGC-1α信号在PPHN中PAEC表型转换和血管生成受损中的作用拟议研究将在患有产前动脉导管收缩诱导的PPHN的胎羊中进行， PPHN机制这些研究的完成将阐明肺动脉压升高的机制。 PPHN血管阻力这些研究还将为测试治疗性增加LKB 1- PGC-1α信号传导和细胞可渗透代谢中间体的药物， PPHN血管生成。