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Role of aquaporins in mammalian lens development,transparency and homeostasis

水通道蛋白在哺乳动物晶状体发育、透明度和稳态中的作用

基本信息

批准号：
9926506
负责人：
Kulandaiappan Varadaraj
金额：
$ 5.9万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926506
关键词：
Adult Age Animal Model Architecture Bilateral Biochemical Biological Biomechanics C-terminal Calcium Cataract Cell Adhesion Cell Adhesion Molecules Cell Culture Techniques Cell Nucleus Cell Volumes Cell membrane Cells Cleaved cell Connexins Coupling Crystallins Cytology Data Defect Development Diabetes Mellitus Disease Embryo Epithelial Cells Equilibrium Event Expression Profiling Eye Filament Gap Junctions Glaucoma Goals Grant Homeostasis Human Hydrostatic Pressure Hyperglycemia In Vitro Individual Ions Knock-in Knock-in Mouse Knock-out Knockout Mice Lead Lens Fiber Lens development MIP gene Macular degeneration Mammals Metabolic Methods Microcirculation Microscopy Modeling Molecular Mus Mutation N-terminal Organ Culture Techniques Osmoregulation Permeability Physiological Play Prevention Proteins Refractive Indices Regulation Retinal Detachment Retinal Diseases Review Literature Risk Role Stress Structure Swelling Testing Thinness Vision Water Work age related base cohesion diabetic experimental study eye dryness fiber cell filensin in vivo insight knockout gene lens lens cortex lens transparency mouse model mutant novel novel therapeutics preservation protein expression response solute treatment strategy wasting water channel

项目摘要

Project Summary Transmembrane water channels known as aquaporins (AQPs) play significant roles in maintaining transparency, biomechanics, refractive index gradient (RING) and homeostasis in the avascular mammalian lens. To get nourishment and eliminate metabolic wastes, the lens creates a microcirculatory current involving AQPs, ion- and solute transporters, and cotransporters. Mutations in fiber cell-specific AQP0, and knockout (KO) of the gene resulted in lens cataract whereas those of epithelial cell-specific AQP1 did not cause any obvious defects in mouse lens under normal physiological conditions. However, lenses of AQP1 KO and AQP5 KO mice developed osmotic swelling and cataract under hyperglycemic stress conditions. Several lens proteins such as beaded filament proteins (CP49 and filensin), crystallins and connexins interact with AQP0, possibly to modulate its functions. The goal here is to elucidate the mechanisms by which the three AQPs, AQP0, AQP1 and AQP5, play important roles to elicit and maintain lens transparency, RING and homeostasis under normal and stressful conditions (such as diabetes). Our long term objective is to contribute to the prevention and treatment of cataracts. The main hypothesis is: Aquaporins play critical roles in the lens microcirculation, biomechanics, RING and osmoregulation, and alterations in their function(s) lead to cataracts. The Specific Aims are to: 1. To explore whether a combination of a decreasing gradient of intact and an increasing gradient of end cleaved forms of AQP0, from the cortex to the nucleus, is required for maintaining lens transparency, biomechanics and RING in vivo. 2. To test whether both water permeability and CTCA functions are critical for maintaining lens transparency, biomechanics and RING, as well as, to explore in vitro, in vivo and ex vivo the molecular mechanism by which AQP0 exerts CTCA between the lens fiber cells. 3. To investigate if regulation of AQP0, AQP1 and AQP5 plays significant roles in maintaining lens osmoregulation and RING for transparency, biomechanics and homeostasis under normal and diabetic hyperglycemic stress conditions. The objectives will be pursued using structure-function approach, as appropriate, and performing microscopy, cell culture, organ culture as well as cytological, biomechanical, biochemical, physiological, and molecular biological experiments along with developing an animal model. The proposed studies have the potential to gather significant data and key information on the mechanistics of the roles played by AQPs in lens transparency and homeostasis. The results could offer new directions for novel therapeutic strategies for the treatment of cataracts and other aquaporin-related diseases in the eye, such as dry eye, glaucoma, retinal detachment, macular degeneration and retinopathy.

项目摘要跨膜水通道被称为水通道蛋白（AQP），在维持细胞内水循环中起着重要作用。透明性、生物力学、折射率梯度（RING）和无血管内稳态哺乳动物的透镜。为了获得营养和排除代谢废物，透镜创造了一个微循环电流，涉及AQPs，离子和溶质转运蛋白和协同转运蛋白。突变在纤维细胞特异性AQP 0中，基因敲除（KO）导致透镜性白内障，而在纤维细胞特异性AQP 0中，上皮细胞特异性AQP 1在正常条件下未引起小鼠透镜的任何明显缺陷生理条件。然而，AQP 1 KO和AQP 5 KO小鼠的晶状体发生渗透性改变，肿胀和白内障。几种透镜蛋白，如珠状蛋白丝蛋白（CP 49和filensin）、晶体蛋白和连接蛋白与AQP 0相互作用，可能调节其功能。本文的目的是阐明这三种AQPs， AQP 0、AQP 1和AQP 5在引起和维持透镜透明性、RING和在正常和压力条件下（如糖尿病）的体内平衡。我们的长远目标是有助于预防和治疗白内障。主要假设是：水通道蛋白发挥作用，在透镜微循环、生物力学、RING和RING调节中的关键作用，以及其功能的改变导致白内障。具体目标是：1.为了探索是否结合完整和 AQP 0的末端裂解形式从皮质到核的梯度增加，保持体内透镜的透明度、生物力学和RING。2.为了测试水是否渗透性和CTCA功能对于维持透镜的透明度、生物力学和 RING，并在体外、体内和离体条件下探讨AQP 0 在透镜纤维细胞之间施加CTCA。3.研究AQP 0、AQP 1和AQP 5的调节在维持透镜调节和RING的透明度、生物力学方面起着重要作用以及在正常和糖尿病高血糖应激条件下的体内平衡。目标是就以下酌情使用结构-功能方法进行，并进行显微镜检查，细胞培养，器官培养以及细胞学、生物力学、生物化学、生理学和分子生物学生物学实验沿着动物模型的开发。拟议的研究包括有可能收集关于以下方面所起作用的机制的重要数据和关键信息：水通道蛋白在透镜透明度和稳态中的作用。这些结果可以为新的研究提供新的方向。用于治疗白内障和其他眼内水通道蛋白相关疾病的治疗策略，例如干眼、青光眼、视网膜脱离、黄斑变性和视网膜病。