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Role of Arginase 1 in Retinal Ischemia-Reperfusion Injury

精氨酸酶 1 在视网膜缺血再灌注损伤中的作用

基本信息

批准号：
10553202
负责人：
Abdelrahman Fouda
金额：
$ 24.9万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553202
关键词：
ARG2 gene Abbreviations Academia Anabolism Arginine Award Bioenergetics Blindness Blood Vessels Career Mobility Cells Cessation of life Chronic Clinical Data Diabetic Retinopathy Disease Enzymes Flow Cytometry Functional disorder Genetic Transcription Glaucoma Goals Grant HDAC3 gene Histone Deacetylase Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Institution Interleukin-1 beta Investigational Drugs Ischemia Knockout Mice Knowledge Laboratories Laboratory Finding Macrophage Mass Spectrum Analysis Mediating Mediator Mentors Metabolic Metabolism Mission Mitochondria Mus Myelogenous Myeloid Cells NOS2A gene Nerve Degeneration Neuronal Injury Nitric Oxide Nitric Oxide Synthase Ornithine Ornithine Decarboxylase Outcome Oxidative Stress Paper Pathologic Processes Pathology Pathway interactions Pattern Phase Phenotype Polyamines Production Protein Isoforms Publishing Putrescine Recombinants Reperfusion Injury Reperfusion Therapy Research Research Personnel Research Support Retina Retinal Diseases Retinopathy of Prematurity Role Science Secure Signal Transduction Stress TNF gene Testing Therapeutic Training Translating Translational Research Up-Regulation Urea Vascular Diseases Vision Disorders Vision research arginase arm career career development chromatin modification diabetic effective therapy in vivo inhibitor ischemic injury knock-down neuroprotection neurovascular neurovascular injury new therapeutic target novel novel therapeutics programs protective effect repair function research study retinal ischemia retinal neuron skill acquisition urea cycle vascular injury vein occlusion vision science

项目摘要

PROJECT SUMMARY Retinal ischemia is a major cause of vision loss in common retinal disease conditions including diabetic retinopathy, glaucoma, retinopathy of prematurity, and vein occlusion. This project aims to define the mechanisms of retinal ischemic injury and identify new therapeutic targets. My long-term career goal is to pursue a distinguished career in vision research and academia. I will achieve this through establishing a strong independent research program in an academic institution that promotes interdisciplinary biomedical science and translational research. My short-term goal is to attain intensive training and supervised career development skills that are required for my career transition to become an independent investigator. Securing this award will provide me with the necessary training to achieve my short- term goals and will be the first step towards independence and achieving my long-term goals. My mentor's lab has demonstrated the involvement of the arginase enzyme in retinal neurovascular diseases. Arginase has two isoforms. Building upon the lab's finding that the mitochondrial isoform, arginase 2 (A2), has a deleterious role in retinal ischemia-reperfusion (IR) injury, I developed a project focusing on the neurovascular protective role of the cytosolic isoform arginase 1 (A1). My recently published paper shows a neuroprotective role of A1 expression in myeloid cells. Arginase competes with nitric oxide synthase (NOS) for their common substrate L-arginine. Nitric oxide (NO) produced by inducible NOS (iNOS) causes neurovascular degeneration. I predict that A1 upregulation in myeloid cells limits iNOS-derived nitrative and oxidative stress and reduces inflammation through its downstream metabolites ornithine and putrescine. Putrescine is the precursor of polyamines and it is formed from ornithine by ornithine decarboxylase (ODC, the rate-limiting enzyme in polyamine biosynthesis). These metabolites have been shown to promote reparative myeloid cells through chromatin modification. In line with this, my preliminary data show that histone deacetylase (HDAC) 3 is increased in the absence of A1 in both IR-injured retinas and stimulated macrophages. HDAC3 is essential for macrophage inflammatory gene transcription and it has been shown to suppress A1 expression. Herein, I propose a novel suppressive effect of A1 on HDAC3. My central hypothesis predicts that myeloid A1 protects against retinal IR injury through ODC-mediated suppression of HDAC3. I will be using mice with myeloid-specific deletion of A1, ODC and HDAC3, as well as the investigational drug, BCT-100 (a PEGylated form of arginase 1), together with primary macrophages isolation and treatment with inhibitors for HDAC3 or arginase downstream enzyme, ODC. My goal is to achieve the following objectives: A) Determine the effect of manipulating the arginase pathway on myeloid cells infiltration / activation in retinal IR injury and the therapeutic potential of BCT- 100. B) Describe the cross talk between the arginase pathway and HDAC3 and determine whether A1 in myeloid cells mediates its protective effect through suppression of HDAC3.

项目摘要视网膜缺血是糖尿病等常见视网膜疾病视力丧失的主要原因视网膜病、青光眼、早产儿视网膜病和静脉阻塞。该项目旨在定义视网膜缺血性损伤的机制，并确定新的治疗靶点。我的长期职业目标是在视觉研究和学术界追求卓越的职业生涯。我会通过在学术机构中建立强大的独立研究计划来实现这一目标，促进跨学科生物医学科学和转化研究。我的短期目标是达到培训和监督的职业发展技能，这是我的职业过渡所需的，成为一个独立调查员获得这个奖项将为我提供必要的培训，以实现我的短期- 这将是我走向独立和实现长期目标的第一步。我导师的实验室已经证明了视网膜神经血管炎中的酶疾病精氨酸酶有两种亚型。基于实验室的发现，线粒体同工酶2 (A2)，在视网膜缺血再灌注（IR）损伤中具有有害作用，我开发了一个专注于胞质异构体脱氢酶1（A1）的神经血管保护作用。我最近发表的论文显示， A1在髓样细胞中表达的神经保护作用。精氨酸酶与一氧化氮合酶（NOS）竞争它们的共同底物L-精氨酸。诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）引起神经血管退化我预测骨髓细胞中A1的上调限制了iNOS衍生的硝化和氧化应激并通过其下游代谢物鸟氨酸和腐胺减轻炎症。腐胺是它是多胺的前体，并且通过鸟氨酸脱羧酶（ODC，限速酶）由鸟氨酸形成。多胺生物合成中的酶）。这些代谢物已被证明可以促进骨髓细胞的修复通过染色质修饰。与此一致，我的初步数据显示，组蛋白去乙酰化酶（HDAC）3是增加的情况下，A1在IR损伤的视网膜和刺激的巨噬细胞。HDAC 3是必不可少的巨噬细胞炎性基因转录，并已显示抑制A1表达。在此，我提出了A1对HDAC 3的新的抑制作用。我的中心假设预测，髓样A1保护通过ODC介导的HDAC 3抑制来对抗视网膜IR损伤。我将使用骨髓特异性 A1、ODC和HDAC 3的缺失，以及研究药物BCT-100（一种PEG化形式的腺苷酸酶 1），连同原代巨噬细胞分离和用HDAC 3或HDAC酶下游抑制剂处理酶，ODC。我的目标是实现以下目标：A）确定操纵的效果视网膜IR损伤中髓样细胞浸润/活化的激酶途径和BCT的治疗潜力- 100. B）描述淀粉酶途径和HDAC 3之间的串扰，并确定髓样细胞中的A1是否与HDAC 3相关。细胞通过抑制HDAC 3介导其保护作用。