Role of Runx1 in Pathologic Ocular Angiogenesis

Runx1 在病理性眼血管生成中的作用

• 批准号: 10405616
• 负责人: LEO A KIM
• 金额: $ 50.22万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405616
• 关键词: Affect; Age; Age related macular degeneration; Area; Atrophic; Binding Sites; Bioinformatics; Blindness; Blood Vessels; Cell physiology; Choroidal Neovascularization; Chronic; Clinical; Data; Defect; Development; Disease; Elderly; Endothelial Cells; Exudative age-related macular degeneration; Eye; Eye diseases; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Transcription; Glucose; Human; In Vitro; Infant; Injections; Lasers; Lead; Light Coagulation; Mediating; Mediator of activation protein; Membrane; Methodology; Methods; Modality; Modeling; Molecular; Mus; Ontology; Oxygen; Pathologic; Pathologic Neovascularization; Pathway interactions; Patients; Physiologic Neovascularization; Physiological; Premature Infant; Process; Proteins; Publishing; Research; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Risk; Role; Sequence Analysis; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcriptional Regulation; Treatment Factor; United States; Validation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vision; acute myeloid leukemia 1 protein; angiogenesis; base; bioinformatics tool; demographics; differential expression; experimental study; gain of function; in vivo; knock-down; loss of function; man; migration; mouse model; neovascularization; novel; ocular angiogenesis; ocular neovascularization; overexpression; patient subsets; postnatal; postnatal development; preclinical efficacy; proliferative diabetic retinopathy; retina blood vessel structure; screening; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; translational potential

PROJECT SUMMARY Pathologic ocular angiogenesis is the underlying mechanism of a variety of sight threatening diseases of the eye affecting a wide range of patients including premature infants and the elderly. Retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and exudative age-related macular degeneration (wet AMD) are common causes of blindness in infants, working age, and the elderly respectively. These conditions are primarily characterized by aberrant neovascularization, or the formation of vascular membranes on top or below the retina. We performed transcriptome analysis of vascular endothelial cells (ECs) obtained from fibrovascular membranes (FVMs) from patients with PDR, and identified Runt-related transcription factor 1 (Runx1) as a gene that is upregulated in pathologic ocular angiogenesis. We subsequently showed that Runx1 mediated EC function, and that its inhibition leads to a reduction in aberrant angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). Based on these data, we hypothesize that Runx1-mediated angiogenesis is an important mechanism for aberrant angiogenesis within the eye, and that Runx1 inhibition is a potential therapeutic modality for the treatment of a wide array of pathologic angiogenic diseases. To test this hypothesis, the following research aims are proposed: Aim 1. To determine the role of Runx1 in physiological and pathological angiogenesis using genetic models of Runx1 loss- and gain-of-function: Using inducible models of Runx1 loss- and gain-of-function (LOF/GOF), we will evaluate the role of Runx1 in both physiological and pathological angiogenesis. We will look at postnatal development of the retinal vessels, as well as pathologic angiogenesis using laser-induced choroidal neovascularization (CNV). Aim 2. To determine the downstream effectors of Runx1 transcriptional activity. Using transcriptome analysis, we propose to identify genes that are potentially regulated by Runx1 using human retinal microvascular endothelial cells and Runx1 LOF/GOF models. Using a combination of bioinformatics screening methodologies (gene ontology analysis, Runx1 regulatory sequence analysis, and comparison to our published human PDR transcriptomes) and in vitro validation of gene targets, we propose to identify the direct/indirect downstream mediators that regulate Runx1-mediated angiogenesis. Aim 3. To compare anti-Runx1 versus anti-VEGF treatment in genetic and inducible models of pathologic ocular angiogenesis. Anti-Runx1 therapy has potential benefits over anti-VEGF therapy. In this aim, we propose to compare anti-Runx1 versus anti-VEGF therapy alone or in combination using multiple models of angiogenesis: OIR, Akimba, and laser-induced CNV. Thus this aim will elucidate the translational potential of anti-Runx1 therapy for the management of such diseases as ROP, PDR, and wet AMD.

项目概要 病理性眼部血管生成是多种威胁视力的疾病的潜在机制 眼睛影响范围广泛的患者，包括早产儿和老年人。早产儿视网膜病变 (ROP)、增殖性糖尿病视网膜病变 (PDR) 和渗出性年龄相关性黄斑变性（湿性 AMD） 分别是婴儿、工作年龄和老年人失明的常​​见原因。这些条件是 主要特征是异常的新生血管形成，或顶部或顶部血管膜的形成 视网膜下方。我们对从以下来源获得的血管内皮细胞（EC）进行了转录组分析 来自 PDR 患者的纤维血管膜 (FVM)，并鉴定出 Runt 相关转录因子 1 (Runx1) 作为一种在病理性眼血管生成中上调的基因。我们随后证明了 Runx1 介导的 EC 功能，并且其抑制导致小鼠模型中异常血管生成的减少 氧诱发的视网膜病变（OIR）。基于这些数据，我们假设 Runx1 介导的血管生成是 Runx1 抑制是眼内异常血管生成的一个重要机制 用于治疗多种病理性血管生成疾病的治疗方式。为了测试这个 假设，提出以下研究目标： 目的 1. 利用遗传确定 Runx1 在生理和病理血管生成中的作用 Runx1 功能丧失和功能获得的模型：使用 Runx1 功能丧失和功能获得的诱导模型 (LOF/GOF)，我们将评估Runx1在生理和病理血管生成中的作用。我们将 使用激光诱导观察视网膜血管的出生后发育以及病理性血管生成 脉络膜新生血管（CNV）。 目标 2. 确定 Runx1 转录活性的下游效应子。使用转录组 分析后，我们建议使用人视网膜来识别可能受 Runx1 调节的基因 微血管内皮细胞和 Runx1 LOF/GOF 模型。结合生物信息学筛选 方法论（基因本体分析、Runx1 调控序列分析以及与我们已发表的 人类 PDR 转录组）和基因靶标的体外验证，我们建议识别直接/间接 调节 Runx1 介导的血管生成的下游介质。 目标 3. 在遗传和诱导模型中比较抗 Runx1 与抗 VEGF 治疗 病理性眼部血管生成。抗 Runx1 疗法比抗 VEGF 疗法具有潜在益处。在这个 目的，我们建议比较抗 Runx1 与抗 VEGF 单独治疗或联合使用多种治疗 血管生成模型：OIR、Akimba 和激光诱导的 CNV。因此，这一目标将阐明转化 抗 Runx1 疗法在治疗 ROP、PDR 和湿性 AMD 等疾病方面的潜力。

项目成果

Comparison of widefield swept-source optical coherence tomography angiography with ultra-widefield colour fundus photography and fluorescein angiography for detection of lesions in diabetic retinopathy.

宽视场扫源光学相干断层扫描血管造影与超宽视场彩色眼底摄影和荧光素血管造影检测糖尿病视网膜病变病变的比较。

• DOI: 10.1136/bjophthalmol-2020-316245
• 发表时间: 2021-04
• 期刊: BRITISH JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.1
• 作者: Cui, Ying;Zhu, Ying;Wang, Jay C.;Lu, Yifan;Zeng, Rebecca;Katz, Raviv;Vingopoulos, Filippos;Le, Rongrong;Lains, Ines;Wu, David M.;Eliott, Dean;Vavvas, Demetrios G.;Husain, Deeba;Miller, Joan W.;Kim, Leo A.;Miller, John B.
• 通讯作者: Miller, John B.

Detection of neovascularisation in the vitreoretinal interface slab using widefield swept-source optical coherence tomography angiography in diabetic retinopathy.

• DOI: 10.1136/bjophthalmol-2020-317983
• 发表时间: 2022-04
• 期刊: BRITISH JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.1
• 作者: Lu, Edward S.;Cui, Ying;Le, Rongrong;Zhu, Ying;Wang, Jay C.;Lains, Ines;Katz, Raviv;Lu, Yifan;Zeng, Rebecca;Garg, Itika;Wu, David M.;Eliott, Dean;Vavvas, Demetrios G.;Husain, Deeba;Miller, Joan W.;Kim, Leo A.;Miller, John B.
• 通讯作者: Miller, John B.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

• DOI: 10.1038/s41591-023-02318-3
• 发表时间: 2023-05
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Lopera, Francisco;Marino, Claudia;Chandrahas, Anita S.;O'Hare, Michael;Villalba-Moreno, Nelson David;Aguillon, David;Baena, Ana;Sanchez, Justin S.;Vila-Castelar, Clara;Ramirez Gomez, Liliana;Chmielewska, Natalia;Oliveira, Gabriel M.;Littau, Jessica Lisa;Hartmann, Kristin;Park, Kyungeun;Krasemann, Susanne;Glatzel, Markus;Schoemaker, Dorothee;Gonzalez-Buendia, Lucia;Delgado-Tirado, Santiago;Arevalo-Alquichire, Said;Saez-Torres, Kahira L.;Amarnani, Dhanesh;Kim, Leo A.;Mazzarino, Randall C.;Gordon, Harper;Bocanegra, Yamile;Villegas, Andres;Gai, Xiaowu;Bootwalla, Moiz;Ji, Jianling;Shen, Lishuang;Kosik, Kenneth S.;Su, Yi;Chen, Yinghua;Schultz, Aaron;Sperling, Reisa A.;Johnson, Keith;Reiman, Eric M.;Sepulveda-Falla, Diego;Arboleda-Velasquez, Joseph F.;Quiroz, Yakeel T.
• 通讯作者: Quiroz, Yakeel T.

Divergent Metabolomic Signatures of TGFβ2 and TNFα in the Induction of Retinal Epithelial-Mesenchymal Transition.

• DOI: 10.3390/metabo13020213
• 发表时间: 2023-01-31
• 期刊: Metabolites
• 影响因子: 4.1

Widefield Swept-Source OCT Angiography Metrics Associated with the Development of Diabetic Vitreous Hemorrhage: A Prospective Study.

• DOI: 10.1016/j.ophtha.2021.02.020
• 发表时间: 2021-09
• 期刊: OPHTHALMOLOGY
• 影响因子: 13.7
• 作者: Cui, Ying;Zhu, Ying;Lu, Edward S.;Le, Rongrong;Lains, Ines;Katz, Raviv;Wang, Jay C.;Garg, Itika;Lu, Yifan;Zeng, Rebecca;Eliott, Dean;Vavvas, Demetrios G.;Husain, Deeba;Miller, Joan W.;Kim, Leo A.;Wu, David M.;Miller, John B.
• 通讯作者: Miller, John B.