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（Fe-S）簇是促进线粒体呼吸并受 Fe-S 调节的假体基团。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。 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，并受到 miR-130/301 家族/PPARγ 调节轴的控制。 Fe-S 缺乏，特别是肺血管内皮细胞缺乏，是 PH 的关键致病关键，也是遗传性疾病和获得性疾病触发因素的共同汇合点，我们计划对这两者进行研究。啮齿类动物和人类体内的 PH 起源，即基于 microRNA 的 ISCU/FXN 协调调节，以及 ISCU 和 FXN 的人类遗传缺陷。 具体目标：1) 确定 miR-。在 PH 的缺氧小鼠模型和培养的肺血管内皮细胞中，130/301 家族抑制 FXN 和 Fe-S 表达以控制 PH。结合患病小鼠的新生物物理测定法来测量 Fe-S 水平，我们将检验 miR-130/301 家族下调 FXN 以抑制 Fe-S 生物合成和线粒体呼吸从而促进 PH 的假设。确定 FXN 的 miR-130/301 依赖性控制是代谢功能障碍和 PH 总体控制中 miR-210/ISCU 轴的关键补充 2)。确定 miR-210 和 miR-130/301 的上调共同促进 Fe-S 簇表达的下调是否比单独使用任一 miRNA 更强烈，并且 PH 表现更严重，我们将使用上述模型系统来检验以下假设： miR-210 和 miR-130/301 的上调共同促进 Fe-S 完整性的更强烈下调和 PH 严重程度的增加，结果对于制定协同治疗靶向的路线图非常有价值。 3) 确定人类 ISCU 和 FXN 的突变是否直接促进 PH。 为了评估人类 FXN 或 ISCU 遗传缺陷而不缺氧的 PH，我们计划进行先进的心肺运动测试。特定的诱导多能干细胞来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组合应该可以确定 Fe-S 缺乏症的 PH 风险，指导临床护理和治疗。巩固这一范式在人类中的相关性。 意义：该提案结合了铁硫生物学领域严格的专业知识和新技术进步，以及将机制发现直接转化为人类的难得机会，我们的目标是坚定地将铁硫缺乏作为一种强大的新型代谢疾病起源，一种新的治疗方法。 PH 的目标，并为发现具有类似缺氧和代谢基础的其他疾病奠定了基础。