Impaired mitochondrial fusion in pulmonary arterial hypertension

肺动脉高压线粒体融合受损

基本信息

批准号：
7813587
负责人：
STEPHEN L ARCHER
金额：
$ 50万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7813587
关键词：
Address Apoptosis Area Arterial Injury Award Basic Science Blood Circulation Blood Platelets Blood Vessels Cell Proliferation Cell Respiration Cells Clinical Research Cobalt Consumption Data Dichloroacetate Disease susceptibility Dose Down-Regulation Endothelium Environment Equilibrium Genes Glycolysis Grant Growth Human Hydrogen Peroxide Hyperplasia Hypoxia Hypoxia Inducible Factor Inflammation Injection of therapeutic agent Investigational Therapies Lead Link Lung Lung diseases Mediating Medicine Membrane Potentials Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Names Oxidation-Reduction PDH kinase Pathogenesis Pathology Phenotype Play Positron-Emission Tomography Process Production Proteins Pulmonary Hypertension Pulmonary artery structure Rattus Respiration Reticulum Role Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Structure Supplementation Suppressor Genes Syndrome Therapeutic Time Tunica Adventitia Vascular remodeling cell growth fluorodeoxyglucose gene therapy in vivo kinase inhibitor mitochondrial DNA mutation mitochondrial membrane mortality overexpression oxidant stress public health relevance pulmonary arterial hypertension therapeutic target therapy development transcription factor uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): This proposal responds to the broad challenge area (04): Clinical Research and specific challenge topic 04-HL-102: Develop Integrative Strategies to Elucidate the Mechanisms of Lung Diseases. Pulmonary arterial hypertension (PAH) is a syndrome characterized by obstructive vascular remodeling, inflammation and vasoconstriction of small pulmonary arteries. Despite recent therapeutic advances, 1-year mortality rates remains high (~15%). Although abnormalities of the platelets, endothelium and adventitia contribute critically to the pathogenesis of PAH, excessive proliferation of pulmonary arterial smooth muscle cells (PASMC) is a major contributor to the obstructive vascular pathology. This challenge proposal explores 2 newly-recognized abnormalities that promote PASMC proliferation. We recently discovered that the mitochondrial network is disrupted in PAH PASMC and noted that this is related to the proliferative diathesis of these cells. Fragmentation of the mitochondrial network appears to reflect impaired mitochondrial fusion and is associated with 2 related abnormalities: 1) normoxic activation of the master hypoxic transcription factor, hypoxia inducible factor (HIF-1a) and 2) downregulation of mitofusin-2. Normally, mitochondria rapidly join and break apart through highly regulated processes called fusion and fission, respectively. The balance of fusion and fission dynamically regulates the integrity of the reticulum. Fusion is regulated by SNARE-like proteins called mitofusin-1 and mitofusin-2. Fusion redistributes mitochondrial proteins/genes, protecting the cell from oxidant stress, apoptosis and mitochondrial DNA mutations. Impaired fusion alters mitochondrial membrane potential, impairs respiration and promotes SMC proliferation. We evaluate the hypothesis that a HIF-1a-mediated mitofusin-2 deficiency promotes PASMC proliferation and contributes to PAH. Relevant to PAH, mitofusin-2 is a brake on SMC proliferation. Indeed, when first cloned, mitofusin-2 was named hyperplasia suppressor gene. Mitofusin-2 gene therapy reduces intimal hyperplasia in a systemic arterial injury model. HIF-1a is known to downregulate mitofusin-2 expression. Impaired fusion and normoxic HIF-1a activation are found in humans with PAH and fawn-hooded rats (FHR), a strain that spontaneously develops PAH. PUBLIC HEALTH RELEVANCE: We are investigating the mechanism of pulmonary arterial hypertension (PAH) in Fawn Hooded Rats (FHR), and have identified problems in the FHR's mitochondria, namely lower production of hydrogen peroxide and fragmentation of the mitochondrial network, which create a pseudohypoxic environment that favors rapid cell growth and blood vessel blockage. Preliminary studies show that FHR suffer from activation of an hypoxia inducible factor" (HIF-1a) and a related break-up of the mitochondrial network due to a deficiency of mitofusin 2 (which triggers excessive growth of arterial smooth muscle cells and blocks the lung circulation). This proposal seeks to understand the role of the HIF-1a and mitofusin in PAH and develop therapies (inhibition of HIF-1 a and supplementation of mitofusin-2) to restore mitochondrial form and function and cure PAH.

描述（由申请人提供）：该提案对广泛的挑战领域做出回应：临床研究和特定挑战主题04-HL-102：制定综合策略以阐明肺部疾病的机制。肺动脉高压（PAH）是一种综合征，其特征是小肺动脉的阻塞性血管重塑，炎症和血管收缩。尽管最近的治疗进展，但1年死亡率仍然很高（约15％）。尽管血小板，内皮和床位异常的异常有助于PAH的发病机理，但肺动脉平滑肌细胞（PASMC）的过度增殖是阻塞性血管病理学的主要原因。该挑战提案探讨了2种新认识的异常，以促进PASMC的增殖。我们最近发现，线粒体网络在PAH PASMC中被破坏，并指出这与这些细胞的增殖性素质有关。线粒体网络的碎裂似乎反映了线粒体融合受损，并且与2种相关异常有关：1）主缺氧转录因子的差异激活，缺氧诱导因子（HIF-1A）（HIF-1A）和2）下调了介子2的下调。通常，线粒体分别通过称为融合和裂变的高度调节过程迅速加入并分解。融合和裂变的平衡动态调节网状的完整性。融合受称为Mitofusin-1和Mitofusin-2的核心样蛋白来调节。融合重新分布线粒体蛋白/基因，可保护细胞免受氧化应激，凋亡和线粒体DNA突变的影响。融合受损会改变线粒体膜电位，损害呼吸并促进SMC增殖。我们评估了HIF-1A介导的丝线FADIDICAS促进PASMC增殖并有助于PAH的假设。与PAH相关，Mitofusin-2是SMC增殖的刹车。实际上，当第一次克隆时，Mitofusin-2被称为增生抑制基因。丝属蛋白-2基因疗法在全身动脉损伤模型中降低了内膜增生。 HIF-1A已知会下调丝线曲霉-2的表达。在患有PAH和鹿角大鼠（FHR）的人类中发现了融合型和常氧HIF-1A激活，这是一种自发发展PAH的菌株。公共卫生相关性：我们正在调查小鹿帽大鼠（FHR）中肺动脉高压（PAH）的机制，并确定了FHR的线粒体中的问题，即过氧化氢的产生和线粒体网络的碎片产生，从而产生了Pseudohypoxic环境，从而造成了pseudohypoxic Environment，从而产生了较快的细胞增长并造成了失误和失误。 Preliminary studies show that FHR suffer from activation of an hypoxia inducible factor" (HIF-1a) and a related break-up of the mitochondrial network due to a deficiency of mitofusin 2 (which triggers excessive growth of arterial smooth muscle cells and blocks the lung circulation). This proposal seeks to understand the role of the HIF-1a and mitofusin in PAH and develop therapies (inhibition of HIF-1 a并补充介脂蛋白-2），以恢复线粒体形式和功能以及治愈PAH。