Iron-Sulfur Deficiency as a Critical Pathogenic Cause of Pulmonary Hypertension

铁硫缺乏是肺动脉高压的关键致病原因

• 批准号: 9252504
• 负责人: Stephen Y Chan
• 金额: $ 38.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252504
• 关键词: Biogenesis; Biological Assay; Biological Models; Biology; Biophysics; Blood Vessels; Cardiopulmonary; Catheterization; Cells; Chronic; Clinical; Complement; Coupled; Disease; Dissection; Down-Regulation; Electron Spin Resonance Spectroscopy; Electron Transport; Endothelium; Exercise stress test; Family; Foundations; Functional disorder; Genetic; Human; Human Genetics; Hypoxia; Individual; Iron; Knockout Mice; Link; Lung; Measures; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; MicroRNAs; Mitochondria; Modeling; Molecular; Mus; Mutation; PECAM1 gene; PPAR gamma; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Physiological; Pluripotent Stem Cells; Population; Prosthesis; Proteins; Pulmonary Hypertension; Regulation; Repression; Respiration; Risk; Rodent; Role; Severities; Sulfur; Sulofenur; Technology; Testing; Translating; Up-Regulation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; base; clinical care; frataxin; human disease; in vivo; indexing; inhibitor/antagonist; iron deficiency; loss of function; mitochondrial metabolism; mouse model; new therapeutic target; novel; prevent; public health relevance; sensor; therapeutic target

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a deadly vascular disease linked to an enigmatic repression of mitochondrial metabolism. Iron-sulfur (Fe-S) clusters are prosthetic groups that promote mitochondrial respiration and are regulated by the Fe-S assembly proteins ISCU and FXN (frataxin). Yet, the roles of Fe-S clusters in most human diseases including PH are unknown. We found that hypoxia-induced microRNA-210 represses ISCU, promoting Fe-S deficiency, pulmonary vascular metabolic dysregulation, and PH. We also found that FXN is down-regulated in PH and is controlled by the miR-130/301 family/PPARγ regulatory axis. We hypothesize that Fe-S deficiency, particularly in pulmonary vascular endothelium, is a critical pathogenic lynchpin of PH and is a common convergence point of genetic and acquired disease triggers. We plan to study both rodents and humans in vivo, delineating novel Fe-S-based origins of PH - namely, the coordinated microRNA-based regulation of ISCU/FXN by hypoxia and human genetic deficiencies of ISCU and FXN. Specific Aims: 1) Determine whether the miR-130/301 family represses FXN and Fe-S expression in order to control PH. In a hypoxic mouse model of PH and cultured pulmonary vascular endothelial cells from diseased mice coupled with novel biophysical assays to measure Fe-S levels, we will test the hypothesis that the miR-130/301 family down-regulates FXN in order to repress Fe-S biogenesis and mitochondrial respiration and thus promote PH. Such findings would identify miR-130/301-dependent control of FXN as a critical complement to the miR-210/ISCU axis in metabolic dysfunction and in the overall control of PH. 2) Determine whether up-regulation of miR-210 and miR-130/301 together promotes more robust down- regulation of Fe-S cluster expression and more severe PH manifestation than either miRNA alone. Using the model systems above, we will test the hypothesis that up-regulation of miR-210 and miR-130/301 together promote more robust down-regulation of Fe-S integrity and increased PH severity. Results would be invaluable for developing a roadmap for synergistic therapeutic targeting of microRNAs in PH. 3) Determine whether mutations of ISCU and FXN in humans directly promote PH. To assess for PH in human genetic deficiency of FXN or ISCU without hypoxia, we plan advanced cardiopulmonary exercise tests. We will also generate/study patient-specific inducible pluripotent stem cells to determine how the mutations control pulmonary vascular function. This rare combination of molecular study and patient testing should define PH risk in Fe-S deficiency, guiding clinical care and solidifying this paradigm's relevance in humans. Significance: This proposal incorporates rigorous expertise and new technological advancements in Fe-S biology coupled with a rare opportunity to translate mechanistic findings directly to humans. We aim to firmly establish Fe-S deficiency as a powerful and novel metabolic disease origin, a new therapeutic target for PH, and a foundation for discovery in other diseases that share similar hypoxic and metabolic underpinnings.

描述（由申请人提供）：肺动脉高压（PH）是一种致命的血管疾病，与线粒体代谢的神秘抑制有关。铁硫簇是促进线粒体呼吸的辅基，受铁硫组装蛋白ISCU和FXN（共济失调蛋白）的调节。然而，Fe-S簇在包括PH在内的大多数人类疾病中的作用尚不清楚。我们发现缺氧诱导的microRNA-210抑制ISCU，促进Fe-S缺乏，肺血管代谢失调和PH。我们还发现FXN在PH中下调，并受miR-130/301家族/PPARγ调节轴控制。我们假设Fe-S缺乏，特别是肺血管内皮细胞的Fe-S缺乏，是PH的关键致病关键，是遗传和获得性疾病触发因素的共同交汇点。我们计划在体内研究啮齿动物和人类，描绘新的基于Fe-S的PH起源-即，通过缺氧和ISCU和FXN的人类遗传缺陷协调基于microRNA的ISCU/FXN调节。具体目标：1）确定miR-130/301家族是否抑制FXN和Fe-S表达以控制PH。在PH的缺氧小鼠模型和来自患病小鼠的培养的肺血管内皮细胞中，结合新的生物物理测定来测量Fe-S水平，我们将检验miR-130/301家族下调FXN以抑制Fe-2表达的假设。这些发现将确定FXN的miR-130/301依赖性控制作为代谢功能障碍和PH的总体控制中miR-210/ISCU轴的关键补充。210和miR-130/301一起促进Fe-S簇表达的更稳健的下调和比单独的任一种miRNA更严重的PH表现。使用上述模型系统，我们将检验miR-210和miR-130/301的上调共同促进Fe-S完整性的更稳健下调和PH严重程度增加的假设。3）确定人类中ISCU和FXN的突变是否直接促进PH。为了评估人类FXN或ISCU遗传缺陷而无缺氧的PH，我们计划先进的心肺运动测试。我们还将产生/研究患者特异性诱导多能干细胞，以确定突变如何控制肺血管功能。这种罕见的分子研究和患者测试的结合应该定义Fe-S缺乏症的PH风险，指导临床护理并巩固这种范式在人类中的相关性。 重要性：该提案结合了Fe-S生物学的严格专业知识和新技术进步，以及将机械发现直接转化为人类的难得机会。我们的目标是牢固地建立Fe-S缺乏症作为一个强大的和新的代谢性疾病的起源，一个新的治疗目标的PH，并在其他疾病的发现共享类似的缺氧和代谢基础的基础。