Frataxin deficiency as a cause of endothelial senescence in multiple subtypes of pulmonary hypertension

Frataxin 缺乏是多种肺动脉高压亚型内皮衰老的原因

• 批准号: 10653917
• 负责人: Stephen Y Chan
• 金额: $ 61.67万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653917
• 关键词: Ataxia; Automobile Driving; Binding; Biogenesis; Blood Vessels; Cardiomyopathies; Cell Aging; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Cellular biology; Classification; Confusion; DNA Damage; Data; Dependovirus; Development; Disease; Dose; Drug Controls; Endothelial Cells; Endothelium; Evolution; Friedreich Ataxia; Functional disorder; Funding; GSTP1 gene; Genetic; Genetically Engineered Mouse; Genomics; Genotoxic Stress; Heart Atrium; Heart Diseases; Hematological Disease; Heterogeneity; Histology; Human; Hypertrophic Cardiomyopathy; Hypoxia; Inflammation; Inflammatory; Interleukin-6; Knock-out; Knockout Mice; Left; Link; Lung; Metabolic dysfunction; Mitochondria; Modeling; Molecular; Mutation; Myelogenous; Myeloid Cells; Nuclear; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Regulation; Reporting; Repression; Rodent; Role; Shapes; Shunt Device; Signal Transduction; Specimen; Stress; Sulfur; Sulofenur; Syndrome; Technology; Telephone; Transgenic Organisms; Vascular Endothelial Cell; Work; analog; cell type; cohort; cytokine; drug efficacy; endothelial stem cell; frataxin; genome editing; hypertension control; improved; in vivo; induced pluripotent stem cell; inhibitor; iron deficiency; mitochondrial metabolism; mouse model; novel; novel therapeutics; prevent; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary vascular remodeling; replication stress; senescence; single-cell RNA sequencing; therapeutic development

Background: Endothelial cell (EC) pathobiology drives pulmonary hypertension (PH), but confusion over the evolution of EC phenotypes in this disease has persisted for decades. EC senescence, a state of stable cell cycle arrest, has been reported in PH, but the regulatory features are unknown. Led by our prior work showing deficiency of iron-sulfur (Fe-S) clusters in PH, we found that a Fe-S biogenesis protein, frataxin (FXN), controls senescence in pulmonary ECs. This may occur in Friedreich’s ataxia (FRDA), a disease marked by genetic FXN deficiency, cardiomyopathy, and often PH. Here, we offer a new model of EC biology in PH, where FXN loss promotes genotoxic stress and senescence in a pulmonary EC subset with low enough FXN. Senescent ECs then promote inflammation and drive many PH subtypes, including PH of FRDA and left heart disease. Hypothesis: We propose FXN deficiency, driven by genetic or acquired means, orchestrates Fe-S-dependent genotoxic stress, enforcing EC senescence and multiple PH subtypes. Aim 1. Determine if FXN deficiency drives DNA damage to enforce EC senescence. By study of human pulmonary artery and microvascular ECs and via genome editing of FXN mutations in inducible pluripotent stem cell (iPSC)-derived ECs from FRDA patients, we will study the role of FXN in genomic stress and EC senescence. Via study of circulating factors, histology, and single cell RNA sequencing, we will assess EC senescence in plasma and rare lung specimens from PAH patients and FRDA and HCM patients with pulmonary vascular disease. We expect to see a dose- dependent orchestration of FXN activities converging on EC senescence and PH. Aim 2. Determine if EC FXN deficiency depends upon senescence and myeloid inflammation to drive PH. In mice models of Groups 1 PAH and Group 2 PH due to FRDA, by using EC FXN-/- (KO) technology and adeno-associated virus delivery of FXN and its binding partner ISCU to pulmonary ECs in vivo, we will assess EC genomic stress, senescence, inflammation, and PH. EC-specific p16 KO mice and CX3CR1 KO mice will be used to define if EC FXN depends upon senescence and downstream myeloid inflammation to control PH. Thus, we aim to prove a new causative model of EC biology in PH – one that deconvolutes the confusion over EC heterogeneity that has plagued this field for decades. Aim 3. Determine if a novel GSTP1 inhibitor increases FXN and reverses multiple PH subtypes. We found that a GSTP1 inhibitor increases FXN and ISCU and improves PH. We will define this drug’s efficacy for ameliorating Groups 1-2 PH models and if FXN and GSTP1 are crucial for its function (via FXN and GSTP1/2 KO mice). If so, we could define an entirely new Fe-S-specific therapy for PH and FRDA. Significance: Via unique human and rodent discovery platforms, we will investigate an EC Fe-S cluster- senescence axis controlling multiple PH subtypes. Our work could explain the evolution of EC biology in PH and shift molecular paradigms, particularly for FRDA and Group 2 PH. Our work will also develop new therapies using senolytic drugs to control Fe-S biogenesis, notably applicable to Group 2 PH with no approved treatments.

背景：内皮细胞（EC）病理生物学驱动肺动脉高压（PH），但对内皮细胞（EC）病理生物学的混淆， 这种疾病中EC表型的演变已经持续了几十年。EC衰老，一种稳定的细胞状态 周期停滞，已报告在PH，但监管特点是未知的。在我们之前的工作中， 在PH中缺乏铁硫（Fe-S）簇时，我们发现一种Fe-S生物合成蛋白，共济失调蛋白（FXN）， 肺内皮细胞的衰老。这可能发生在弗里德赖希共济失调（FRDA）中，这是一种以遗传性共济失调为标志的疾病。 在这里，我们提供了一个新的模型EC生物学在PH，其中FXN缺乏症，心肌病，并经常PH。 在FXN足够低的肺EC亚群中，损失促进遗传毒性应激和衰老。衰老 然后，内皮细胞促进炎症并驱动许多PH亚型，包括FRDA和左心疾病的PH。 假设：我们提出FXN缺乏，由遗传或后天手段驱动，协调Fe-S依赖性 遗传毒性胁迫，加强EC衰老和多种PH亚型。目标1。确定是否存在FXN缺陷 驱动DNA损伤以促进EC衰老。通过对人肺动脉和微血管内皮细胞的研究， 以及通过来自FRDA的诱导性多能干细胞（iPSC）衍生的EC中的FXN突变的基因组编辑， 患者，我们将研究FXN在基因组应激和EC衰老中的作用。通过对循环因素的研究， 组织学和单细胞RNA测序，我们将评估血浆和罕见肺标本中的EC衰老 PAH患者和FRDA和HCM肺血管疾病患者。我们希望看到一剂- FXN活动的依赖性协调集中在EC衰老和PH上。目的2。确定EC FXN是否 缺乏依赖于衰老和骨髓炎症来驱动PH。 通过使用EC FXN-/-（KO）技术和腺相关病毒递送，治疗FRDA引起的PAH和2型PH FXN及其结合伴侣ISCU与肺EC的体内结合，我们将评估EC基因组应激，衰老， EC特异性p16 KO小鼠和CX 3CR 1 KO小鼠将用于确定EC FXN是否依赖于 因此，我们的目标是证明一种新的致病因素， PH中EC生物学的模型-一个去卷积EC异质性的混乱，一直困扰着这一点 几十年来的田野目标3。确定新型GSTP 1抑制剂是否增加FXN并逆转多种PH 亚型我们发现GSTP 1抑制剂增加FXN和ISCU并改善PH。 药物改善第1-2组PH模型的疗效，以及FXN和GSTP 1是否对其功能至关重要（通过 FXN和GSTP 1/2 KO小鼠）。如果是这样，我们可以定义一种全新的Fe-S特异性疗法来治疗PH和FRDA。 意义：通过独特的人类和啮齿动物发现平台，我们将研究EC Fe-S簇- 衰老轴控制多种PH亚型。我们的工作可以解释pH值对EC生物学的影响 并改变分子模式，特别是FRDA和第2组PH。我们的工作还将开发新的治疗方法 使用衰老清除药物控制Fe-S生物发生，特别适用于未经批准治疗的第2组PH。

项目成果

The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.

miR-200家族调节双质主动脉瓣升主动脉的关键致病事件。

• DOI: 10.1111/joim.12833
• 发表时间: 2019-01
• 期刊: Journal of internal medicine
• 影响因子: 11.1
• 作者: Maleki S;Cottrill KA;Poujade FA;Bhattachariya A;Bergman O;Gådin JR;Simon N;Lundströmer K;Franco-Cereceda A;Björck HM;Chan SY;Eriksson P
• 通讯作者: Eriksson P

Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.

• DOI: 10.1183/16000617.0094-2017
• 发表时间: 2017-12-31
• 期刊: European respiratory review : an official journal of the European Respiratory Society
• 作者: Chan SY;Rubin LJ
• 通讯作者: Rubin LJ

Treatment of exercise pulmonary hypertension improves pulmonary vascular distensibility.

• DOI: 10.1177/2045894018787381
• 发表时间: 2018-07
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Wallace WD;Nouraie M;Chan SY;Risbano MG
• 通讯作者: Risbano MG

Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.

• DOI: 10.15252/emmm.201404511
• 发表时间: 2015-06
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: White K;Lu Y;Annis S;Hale AE;Chau BN;Dahlman JE;Hemann C;Opotowsky AR;Vargas SO;Rosas I;Perrella MA;Osorio JC;Haley KJ;Graham BB;Kumar R;Saggar R;Saggar R;Wallace WD;Ross DJ;Khan OF;Bader A;Gochuico BR;Matar M;Polach K;Johannessen NM;Prosser HM;Anderson DG;Langer R;Zweier JL;Bindoff LA;Systrom D;Waxman AB;Jin RC;Chan SY
• 通讯作者: Chan SY

Effects of ranolazine on right ventricular function, fluid dynamics, and metabolism in patients with precapillary pulmonary hypertension: insights from a longitudinal, randomized, double-blinded, placebo controlled, multicenter study.

• DOI: 10.3389/fcvm.2023.1118796
• 发表时间: 2023
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Han, Q. Joyce;Forfia, Paul;Vaidya, Anjali;Ramani, Gautam;deKemp, Robert A.;Mach, Robert H.;Mankoff, David A.;Bravo, Paco E.;DiCarli, Marcelo;Chan, Stephen Y.;Waxman, Aaron B.;Han, Yuchi
• 通讯作者: Han, Yuchi