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（由适用提供）：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表达有关。铁硫（FE-S）簇是促进线粒体呼吸的假体群，并由Fe-S组装蛋白ISCU和FXN（Frataxin）（Frataxin）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复制品ISCU，促进Fe-S缺乏，肺血管代谢失调和pH。我们还发现，FXN在pH中被下调，并由miR-130/301家族/PPARγ调节轴控制。我们假设Fe-S缺乏，尤其是在肺部血管森林中，是PH的关键致病林奇宾，是遗传和获得性疾病触发因素的常见收敛点。我们计划在体内研究啮齿动物和人类，描述了pH的基于Fe-S的新型起源 - 即，通过缺氧和ISCU和FXN的人类遗传缺陷对ISCU/FXN进行了协调的MicroRNA调节。具体目的：1）确定miR-130/301家族复制品FXN和Fe-S表达是否以控制pH。在pH和培养的肺血管内皮细胞的低氧小鼠模型中，与新型生物物理测定相连以测量Fe-S水平，我们将测试MiR-130/301家族下调FXN以抑制Fe-Sbiogenesis和Mitochrial sectirial sectiration Assiriration and par ph的假设。这样的发现将确定对FXN的miR-130/301依赖性控制是代谢功能障碍和pH的整体控制中对miR-210/iscu轴的临界补体。 2）确定miR-210和miR-130/301的上调是否比单独使用任何miRNA促进了Fe-S簇表达和更严重的pH表现的强大下调。使用上面的模型系统，我们将检验以下假设：MiR-210和miR-130/301的上调促进了Fe-S完整性的更强大下调和pH的严重性增加。结果对于开发协同疗法的路线图将是无价的。在pH中靶向microRNA。 3）确定人类中ISCU和FXN的突变是否直接促进pH。为了评估没有缺氧的FXN或ISCU人类遗传缺乏的pH值，我们计划了晚期心肺运动测试。我们还将生成/研究患者特异性诱导的多能干细胞，以确定突变如何控制肺血管功能。分子研究和患者测试的这种罕见组合应定义Fe-S缺乏症，指导临床护理并巩固该范式在人类中的相关性。 意义：该提案结合了FE-S生物学中的严格专业知识和新的技术进步，再加上很少有机会将机械发现直接转化为人类。我们的目标是首先将FE-S缺乏症作为一种强大而新型的代谢疾病起源，一种新的pH治疗靶点，以及在具有相似低氧和代谢基础的其他疾病中发现的基础。