Trace Element Dynamics in the Vertebrate Eye

脊椎动物眼中的微量元素动力学

基本信息

批准号：
8509689
负责人：
MARY C McGahan
金额：
$ 35.39万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-04-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509689
关键词：
Address Affect Age Age related macular degeneration Amyloid beta-Protein Precursor Antioxidants Blood Blood Circulation Brain Canis familiaris Cataract Cell Death Cell membrane Cell secretion Cells Ceruloplasmin Ciliary epithelium Complex Crystalline Lens Cystine Data Dimensions Disease Elements Environment Epithelial Cells Event Eye Ferritin Fluorescence Glutamates Glutathione Goals Hemorrhage Homeostasis Human Hyperoxia Hypoxia Hypoxia Inducible Factor Incidence Inflammation Iron Knowledge Laboratories Life Location Measurement Metabolism Methodology Modality Nerve Degeneration Neuraxis Neurons Neurotransmitters Ocular Pathology Organ Oxidative Stress Physiological Physiological Processes Physiology Play Positioning Attribute Prevention Process Proteins Recording of previous events Research Design Retina Retinal Degeneration Role Secondary to Seminal Stroke Structure Structure of retinal pigment epithelium System Tissues Trace Elements Vascular Endothelial Growth Factors Work abstracting antiporter base cellular imaging clinically relevant fluorescence microscope hepcidin human TFRC protein hypoxia inducible factor 1 in vitro Model innovation insight iron metabolism lens metal transporting protein 1 novel oxidative damage retinal ischemia therapeutic development tissue/cell culture transcription factor uptake

项目摘要

Abstract Iron is an essential element for normal physiological functions. However, excess it can cause extensive tissue damage and participates in numerous ocular pathologies including cataractogenesis and retinal degenerations such as age-related macular degeneration. The study of ocular iron metabolism has been a focus of this laboratory for many years. We have made recent novel observations about iron's physiological role. We found that iron regulates synthesis and secretion of the neurotransmitter glutamate by ocular tissues and neurons. This is of fundamental clinical relevance since iron and glutamate are both dysregulated in neurodegeneration. In high quantities, glutamate can be excitotoxic in the central nervous system as well as the retina. Additionally, in retinal pigmented epithelial cells (RPE) and lens epithelial cells (LEC) iron regulates the activity of the transcription factor, hypoxia-inducible factor, which in turn regulates the synthesis of dozens of proteins. Our preliminary data indicate that hypoxic conditions stimulate glutamate release, another critically important observation since hypoxic conditions occur in stroke and retinal ischemia. Furthermore, there are profound changes in the structure of the iron storage protein ferritin in lenses that occur with age, cataractogenesis and differentiation. We will continue to explore how these changes affect iron storage in ferritin and the protection against iron damage such storage provides. Unfortunately, little is known about how iron levels are regulated in the eye which is isolated from the systemic circulation by blood ocular barriers (BOB). The proposal's hypothesis is that intraocular tissues have unique and independent systems for regulating iron uptake into and efflux from the eye across the BOBs. Their polarized location and iron-regulated quantity within ocular tissues allows for proper control of intraocular iron levels. Hypoxia, hemorrhage and inflammation significantly impact iron uptake storage, utilization and efflux. The resulting dysregulation of iron metabolism plays a critical role in ocular pathology. We will use an innovative integrated approach to determine how the BOB's regulate iron levels in intraocular tissues. The two specific aims utilize normal and pathological human eyes as well as normal canine eyes and tissue cultures of cells which form the BOBs, e.g., RPE and CE. Additionally, the lens will be used to assess how iron handling strategies adapt for survival in a normally hypoxic environment. We will utilize a state-of-the-art live-cell imaging quantitative fluorescence microscope with total internal reflection fluorescence for quantifying events at the plasma membrane and allow for measurement of dynamic processes underlying these complex interactions in four dimensions (4D) in living cells. It is the goal of this proposal to determine how intraocular iron levels are controlled and the specific role(s) iron has in ocular pathology in order to provide a basis for development of therapeutic modalities needed for prevention and treatment of ocular disease.

抽象的铁是正常生理功能的必需元素。然而，过量可能会导致广泛组织损伤并参与多种眼部病理，包括白内障发生和视网膜变性，例如年龄相关性黄斑变性。眼部铁代谢的研究多年来一直是本实验室的重点。我们最近对铁的生理作用进行了新的观察角色。我们发现铁通过眼调节神经递质谷氨酸的合成和分泌组织和神经元。这具有重要的临床意义，因为铁和谷氨酸都是神经退行性疾病失调。大量的谷氨酸会对中枢神经产生兴奋性毒性系统以及视网膜。此外，在视网膜色素上皮细胞（RPE）和晶状体上皮细胞中 (LEC) 铁调节转录因子、缺氧诱导因子的活性，进而调节数十种蛋白质的合成。我们的初步数据表明，缺氧条件会刺激谷氨酸释放，另一个至关重要的观察结果，因为缺氧条件发生在中风和视网膜缺血。此外，储铁蛋白铁蛋白的结构也发生了深刻的变化。随着年龄、白内障发生和分化而发生的晶状体。我们将继续探索这些变化会影响铁蛋白中铁的储存以及这种储存提供的针对铁损伤的保护。不幸的是，人们对眼睛中的铁含量如何调节知之甚少，因为眼睛与眼睛是隔离的。通过血眼屏障（BOB）进行体循环。该提案的假设是眼内组织拥有独特且独立的系统来调节铁在眼睛中的吸收和流出鲍勃们。它们在眼组织内的极化位置和铁调节量可以适当控制眼内铁水平。缺氧、出血和炎症显着影响铁的吸收储存，利用和流出。由此产生的铁代谢失调在眼部病理学中起着至关重要的作用。我们将使用创新的综合方法来确定 BOB 如何调节铁水平眼内组织。这两个具体目标利用了正常和病态的人眼以及正常的人眼。犬眼和形成 BOB 的细胞组织培养物，例如 RPE 和 CE。此外，镜头将用于评估铁处理策略如何适应正常缺氧环境中的生存。我们将利用最先进的活细胞成像定量荧光显微镜，具有全内部反射荧光用于量化质膜上的事件并允许测量活细胞中四个维度 (4D) 中这些复杂相互作用的动态过程。它是该提案的目标是确定如何控制眼内铁水平以及铁的具体作用具有眼部病理学方面的研究成果，以便为开发所需的治疗方式提供基础预防和治疗眼部疾病。