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

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

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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称为水通道蛋白（AQP）透明度，生物力学，折射率梯度（环）和稳态哺乳动物镜头。为了获取滋养和消除代谢废物，镜头创造了一个涉及AQP，离子和溶质转运蛋白以及共转运蛋白的微循环电流。突变在纤维细胞特异性AQP0中，该基因的基因敲除（KO）导致镜片白内障上皮细胞特异性AQP1在正常情况下不会引起小鼠镜头的任何明显缺陷生理条件。但是，AQP1 KO和AQP5 KO小鼠的镜头发展了渗透在高血糖应激条件下肿胀和白内障。几种透镜蛋白，例如串珠细丝蛋白（CP49和FILENSIN），结晶蛋白和连接素与AQP0相互作用，可能与调节其功能。这里的目标是阐明三个AQP的机制 AQP0，AQP1和AQP5在引起和保持镜头透明度，环和在正常和压力条件下（例如糖尿病）下的稳态。我们的长期目标是有助于预防和治疗白内障。主要假设是：水通道蛋白玩在晶状体微循环，生物力学，环和渗透调节中的关键作用，以及其功能的改变导致白内障。具体目的是：1。探索完整梯度降低和从皮质到核的末端裂解形式的末端梯度越来越多，需要维持晶状体透明度，生物力学和体内环。 2。测试是否两种水渗透性和CTCA功能对于维持晶状体透明度，生物力学和环上的环，体内探索体内和体内的分子机制AQP0 在晶状体纤维细胞之间发挥CTCA。 3。调查AQP0，AQP1和AQP5的调节在维持透镜渗透调节和环的透明度，生物力学方面起着重要作用在正常和糖尿病高血糖应力条件下的体内平衡。目标将是适当地使用结构功能方法进行显微镜，细胞培养，器官培养以及细胞学，生物力学，生化，生理和分子生物实验以及开发动物模型。拟议的研究具有潜力收集有关角色机制的重要数据和关键信息镜头透明度和稳态的AQP。结果可以为新颖的新指示提供眼睛中白内障和其他与水通道蛋白有关疾病的治疗策略，例如干眼，青光眼，视网膜脱离，黄斑变性和视网膜病变。