Ferrochelatase as a mediator of ocular angiogenesis

铁螯合酶作为眼血管生成的介质

基本信息

批准号：
10750462
负责人：
Timothy W Corson
金额：
$ 44.76万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750462
关键词：
Address Age related macular degeneration Angiogenesis Inhibitors Biology Blindness Carbon Cell physiology Cellular biology Cementation Characteristics Chemicals Choroidal Neovascularization Data Development Disease Down-Regulation Drug Kinetics Dysmorphology Endothelial Cells Enzyme Inhibition Enzymes Exudative age-related macular degeneration Eye Eye diseases Genetic Transcription Genus Hippocampus Glucose Glycolysis Goals Grant Heme Hemeproteins Human Impairment In Vitro Ions Knowledge Lasers Lead Link Longevity Mediating Mediator Metabolic Metabolic Pathway Metabolism Mission Mitochondria Modeling Mus Mutation National Eye Institute Natural Products Nucleotides Oral Oxidative Phosphorylation Oxygen Pathologic Neovascularization Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Process Production Proliferating Proteins Proteome Public Health Publishing Reactive Oxygen Species Regulation Research Research Support Retina Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Specificity Testing Therapeutic Therapeutic Effect Therapeutic Intervention Toxic effect Transcriptional Regulation Vascular Endothelial Growth Factors Work angiogenesis burden of illness cell type cofactor common treatment complex IV cytochrome c oxidase efficacy testing enzyme pathway ferrochelatase heme biosynthesis high throughput screening in vivo in vivo Model inhibitor innovation knock-down mRNA Expression metabolomics mitochondrial dysfunction mouse model neovascular neovascularization novel nucleotide metabolism ocular angiogenesis ocular neovascularization prevent proliferative diabetic retinopathy protoporphyrin IX small molecule stable isotope success synergism targeted treatment therapeutic target tool

项目摘要

The neovascular eye diseases retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular age-related macular degeneration are major causes of blindness through the lifespan. Not all patients respond to existing therapies, so there is thus a critical need to find novel cellular components that could be targeted to block the pathological angiogenesis that is characteristic of these diseases. Ferrochelatase (FECH) is one such component, necessary for proliferation of endothelial cells in vitro and in vivo. FECH is responsible for inserting ferrous ion into protoporphyrin IX, the final step in heme biosynthesis. The previous grant period yielded findings that FECH is upregulated in murine and human choroidal and retinal neovascularization, that FECH inhibition leads to depletion of hemoproteins in endothelial cells, and that FECH loss blocks heme- dependent oxidative phosphorylation in endothelial cells. Reduced FECH activity also surprisingly blocks glycolysis. In addition, the first drug-like FECH inhibitor, SH-17023 was developed and shown to be antiangiogenic in vitro and in vivo. Building on this work, the current goal is to define the mechanism of how heme synthesis through FECH and glycolysis impacts endothelial cell biology and neovascularization. The rationale for this research is that FECH is a significant mediator of angiogenesis, a potential therapeutic target, and a previously unappreciated regulator of the expression and function of glycolytic enzymes. The overall hypothesis is that FECH, via controlling heme availability, is an integrated master regulator of multiple proangiogenic pathways, including glycolysis. Guided by strong preliminary data, the hypothesis will be tested via two specific aims: 1. Delineate the mechanism of FECH’s influence on glycolysis and angiogenesis. The glycolysis enzymes dysregulated by heme synthesis inhibition in endothelial cells and their heme-dependent transcriptional regulation will be assessed in endothelial cells. Glycolytic function and related metabolic pathways will be assessed by Seahorse, targeted metabolomics, and stable isotope tracing. The influence of this heme-dependent glycolysis regulation on endothelial cell function will be determined, along with the cell- type specificity of this effect. 2. Evaluate the first drug-like small molecule FECH inhibitor in ocular neovascularization. The pharmacokinetics and toxicity of SH-17023 will be quantified. Then, this novel molecule will be tested for efficacy in the oxygen-induced retinopathy, Vldlr-/-, and JR5558 retinal, subretinal, and choroidal neovascularization models, plus synergy with anti-VEGF therapy. Overall, this work is innovative, as it is the first mechanistic study of the links between heme synthesis, glycolysis, and posterior ocular angiogenesis, and the first characterization of direct FECH inhibition with a drug-like small molecule for retinal and choroidal neovascularization. The work is highly significant because it will comprehensively elucidate linkages between heme metabolism and the process of glycolysis, not previously connected, and establish FECH blockade as a viable therapy, leading to development of new ways to prevent blindness.

新血管眼疾病会导致早产，糖尿病性视网膜病和新生血管的视网膜病变与年龄相关的黄斑变性是整个生命周期失明的主要原因。并非所有患者都回应对于现有疗法，因此，需要找到可以针对的新型细胞成分的迫切需要阻止这些疾病特征的病理血管生成。铁胆道酶（Fech）是一个这种成分，是体外和体内内皮细胞增殖所必需的。 Fech负责将亚铁离子插入原源性IX，这是血红素生物合成的最后一步。上一个赠款期提出了Fech在鼠和人类脉络膜和视网膜新血管形成中更新的发现， FECH抑制会导致内皮细胞中血蛋白的耗竭，而FECH损失阻碍了血红素内皮细胞中依赖性氧化物磷酸化。减少的Fech活动也令人惊讶地阻止糖酵解。此外，开发了第一个类似药物的Fech抑制剂SH-17023，并证明是体外和体内的抗血管生成。在这项工作的基础上，目前的目标是定义如何通过FECH和糖酵解的血红素合成会影响内皮细胞生物学和新血管形成。这这项研究的基本原理是Fech是血管生成的重要介体，即潜在的治疗靶标，以及先前未批准的糖酵解酶表达和功能的调节剂。总体假设是Fech通过控制血红素可用性，是多个集成的主调节器促血管生成途径，包括糖酵解。在强大的初步数据的指导下，将检验该假设通过两个具体的目的：1。描述Fech对糖酵解和血管生成的影响的机理。在内皮细胞中血红素合成抑制及其血红素依赖性的血红素合成抑制作用失调的糖酵解酶转录调节将在内皮细胞中进行评估。糖酵解功能和相关代谢途径将由Seahorse，靶向代谢组学和稳定的同位素跟踪评估。影响将确定这种对内皮细胞功能的血红素依赖性糖酵解调节输入此效果的特异性。 2。评估眼部第一个类似药物的小分子抑制剂新血管形成。 SH-17023的药代动力学和毒性将被量化。然后，这本小说分子将在氧诱导的视网膜病，VLDLR - / - 和JR55558视网膜，视网膜下，测试分子测试和脉络膜新血管形成模型，以及抗VEGF疗法的协同作用。总的来说，这项工作是创新，因为它是血红素合成，糖酵解和后部之间联系的首次机械研究眼血管生成，以及用类似药物的小分子的直接FECH抑制作用的首次表征视网膜和脉络膜新生血管形成。这项工作非常重要，因为它将全面阐明血红素代谢与糖酵解过程之间的联系，以前没有连接，并且将FECH封锁作为一种可行的疗法，从而发展出新的方法来防止失明。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antiangiogenic Pterocarpan and Flavonoid Constituents of Erythrina lysistemon.

抗血管生成紫檀素和刺桐的类黄酮成分。

DOI：
10.1021/acs.jnatprod.2c00909
发表时间：
2023
期刊：
Journal of natural products
影响因子：
5.1
作者：
Nassief,SarahM;Amer,MasoudaE;Shawky,Eman;Sishtla,Kamakshi;Mas-Claret,Eduard;Muniyandi,Anbukkarasi;Corson,TimothyW;Mulholland,DulcieA;El-Masry,Sawsan
通讯作者：
El-Masry,Sawsan

Small molecule target identification using photo-affinity chromatography.

使用光亲和色谱法识别小分子靶标。

DOI：
10.1016/bs.mie.2019.02.028
发表时间：
2019
期刊：
Methods in enzymology
影响因子：
0
作者：
Seo,Seung-Yong;Corson,TimothyW
通讯作者：
Corson,TimothyW

Chemical Proteomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for Ocular Neovascularization.

化学蛋白质组学揭示可溶性环氧化物水解酶作为眼部新生血管的治疗靶点。

DOI：
10.1021/acschembio.7b00854
发表时间：
2018
期刊：
ACS chemical biology
影响因子：
4
作者：
Sulaiman,RaniaS;Park,Bomina;SheikPranBabu,SardarPasha;Si,Yubing;Kharwadkar,Rakshin;Mitter,SayakK;Lee,Bit;Sun,Wei;Qi,Xiaoping;Boulton,MichaelE;Meroueh,SamyO;Fei,Xiang;Seo,Seung-Yong;Corson,TimothyW
通讯作者：
Corson,TimothyW

Ferrochelatase regulates retinal neovascularization.

DOI：
10.1096/fj.202000964r
发表时间：
2020-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Pran Babu SPS;White D;Corson TW
通讯作者：
Corson TW

The Antiangiogenic Activity of Naturally Occurring and Synthetic Homoisoflavonoids from the Hyacinthaceae ( sensu APGII).

风信子科天然存在和合成的同异黄酮类化合物（意义 APGII）的抗血管生成活性。

DOI：
10.1021/acs.jnatprod.8b00989
发表时间：
2019
期刊：
Journal of natural products
影响因子：
5.1
作者：
Schwikkard,Sianne;Whitmore,Hannah;Sishtla,Kamakshi;Sulaiman,RaniaS;Shetty,Trupti;Basavarajappa,HaleshaD;Waller,Catherine;Alqahtani,Alaa;Frankemoelle,Lennart;Chapman,Andy;Crouch,Neil;Wetschnig,Wolfgang;Knirsch,Walter;Andriantian
通讯作者：
Andriantian