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（PPHN）的持续性肺动脉高压是一种威胁生命的疾病，由肺血管抵抗在出生时降低。受影响的婴儿是缺氧，有增加死亡风险或长期障碍的生存风险。最近的研究确定了2个关键变化 PPHN肺：（1）肺动脉中线粒体生物发生和氧化磷酸化的降低内皮细胞（PAEC）和（2）血管生成减少，这导致产后失败肺循环的适应。该研究项目的总体目标是确定机制这是PPHN的这两个关键变化的基础。针对该项目进行的初步研究被确定为下降肝激酶B1（LKB1）的表达，这是能量传感器的关键上游调节剂5'AMP激活蛋白 PPHN中的激酶（AMPK）。这种改变有助于降低PGC-1α的表达线粒体生物发生所需的辅助因子。与这些变化一致，线粒体生物发生是相比之下，PPHN内皮细胞中缺氧传感器的水平增加，HIF-1α有所增加，导致糖酵解的增加。 PPHN中的PAEC显示表型中的开关主要是尖端细胞通过增殖的茎细胞。改变的LKB1-PGC-1α信号传导是否有助于这种表型开关是未知的。该应用中提出的研究研究了改善LKB1-PGC-1α的假设信号传导会损害PAEC中的线粒体生物发生，而最终的糖酵解切换改变了PAEC 表型规范在肺发育的关键窗口中损害血管生成。假设将通过2个特定目的测试：（1）研究降低LKB1-PGC-1α信号在受损中的作用线粒体生物发生和PPHN中的HIF-1α水平升高，（2）研究降低的作用 PAEC表型开关中的LKB1-PGC-1α信号传导和PPHN中的血管生成受损。提议研究将在胎儿羔羊中通过PPHN进行。 PPHN机制。这些研究的完成将描述肺部增加的机制 PPHN的血管抗性。这些研究还将为测试治疗提供科学原理增加LKB1 -PGC -1α信号传导和细胞可渗透代谢中间体以恢复的药物 PPHN中的血管生成。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pediatric Pulmonary Hypertension: Definitions, Mechanisms, Diagnosis, and Treatment.

DOI：
10.1002/cphy.c200023
发表时间：
2021-06-30
期刊：
Comprehensive Physiology
影响因子：
5.8
作者：
Mukherjee D;Konduri GG
通讯作者：
Konduri GG

Decreased Cyclic Guanosine Monophosphate-Protein Kinase G Signaling Impairs Angiogenesis in a Lamb Model of Persistent Pulmonary Hypertension of the Newborn.

新生儿持续性肺动脉高压羔羊模型中环磷酸鸟苷-蛋白激酶 G 信号传导的减少会损害血管生成。

DOI：
10.1165/rcmb.2020-0434oc
发表时间：
2021
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Sharma,Megha;Rana,Ujala;Joshi,Chintamani;Michalkiewicz,Teresa;Afolayan,Adeleye;Parchur,Abdul;Joshi,Amit;Teng,Ru-Jeng;Konduri,GirijaG
通讯作者：
Konduri,GirijaG

Decreased AMP-activated protein kinase (AMPK) function and protective effect of metformin in neonatal rat pups exposed to hyperoxia lung injury.