Eph-ephrin signaling in the lens

晶状体中的肝配蛋白信号传导

基本信息

批准号：
10585924
负责人：
Catherine Kehsin Cheng
金额：
$ 46.46万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585924
关键词：
Affect Age Aging Agonist Anterior Biochemical Biomechanics Blindness Cataract Cell Adhesion Molecules Cell Communication Cell Differentiation process Cell Maturation Cell Nucleus Cell membrane Cell-Cell Adhesion Cells Confocal Microscopy Crystalline Lens Cytoskeleton Data Development Disease Electron Microscopy Eph Family Receptors EphA2 Receptor Ephrin-A5 Ephrins Epithelial Cells Fiber Functional disorder Glass Goals Growth Homeostasis Human Immunofluorescence Immunologic In Vitro Knock-out Lead Lens Opacities Lens development Ligand Binding Ligands Link Maps Mass Spectrum Analysis Measures Mediating Molecular Morphology Mus Mutation Normal Cell Nuclear Nutrient Optics Pathology Pathway interactions Patients Pattern Peptides Peripheral Phosphorylation Phosphotransferases Play Population Presbyopia Property Reading Refractive Indices Reporting Role Serine Shapes Signal Pathway Signal Transduction Signaling Molecule Structure Tissues Tyrosine Vision Visual impairment Work World Health Organization age related antagonist epithelial to mesenchymal transition fiber cell in vitro Model lens lens cortex lens transparency mouse model normal aging prevent receptor segregation superresolution microscopy ultra high resolution wasting

项目摘要

Project Summary According to the World Health Organization, age-related lens pathologies are the leading cause of visual impairment in the world. Cataracts, defined as any opacity in the eye lens, remain the leading cause of blindness in the world. Presbyopia is caused by a reduction in the lens’ ability to change shape during focusing (accommodation), and, by extension, the need for reading glasses. Unaddressed presbyopia is the leading cause of visual impairment globally. Decades of study have focused on congenital lens pathologies, and thus, very little is known about the underlying cellular and molecular mechanisms that facilitate lifelong lens homeostasis. Recent studies have reported that mutations of the EphA2 receptor or the ephrin-A5 ligand are associated with variable congenital and age-related cataracts in humans and mice, and these bidirectional signaling molecules are key components for regulating lens cell organization and stability. Our mouse models reveal that loss of EphA2 leads to age-related cortical cataracts similar to human patients with EphA2 dysfunction. We will evaluate cataract progression in our mouse line to study the cellular and molecular changes that occur during cortical cataract formation. We hypothesize that loss of EphA2 results in changes in cytoskeletal structures or cell-cell adhesion of peripheral fiber cells leading to optical discontinuities in the lens cortex. Our new data show that the lens utilizes both canonical ligand-mediated EphA2 bidirectional signaling and non-canonical ligand-independent EphA2 signaling pathways. We hypothesize that canonical EphA2 signaling is required in equatorial epithelial cells while non-canonical EphA2 activation is required for fiber cell differentiation and maturation and that this segregation of receptor activity may explain the large variety of human congenital and age-related cataracts caused by EphA2 mutations. We will evaluate the activation pattern of EphA2 spatially and temporally and determine the activity of known downstream pathways in different lens cell populations. We will apply EphA2 agonist and antagonist peptides to primary culture mouse lens epithelial cells to generate mini lenses as an in vitro model for lens development. Increased size and stiffness of the lens center or nucleus has been hypothesized to be a key factor for not only age-related increases in overall lens stiffness and presbyopia, but also poor nutrient and waste transport leading to age-related nuclear cataracts. Our new preliminary data shows that loss of EphA2 leads to softer, smaller lens nuclei. We hypothesize that Eph-ephrin signaling is required for normal cell-cell adhesion and cytoskeleton rearrangement that drives nuclear fiber cell membrane re-organization and compaction. This data will provide a better understanding of coordinated signaling mechanisms for maintaining homeostasis during normal aging and in lenses with changes in transparency and biomechanical properties, which may lead to the development of new non-surgical approaches to delay or prevent age-related lens pathologies.

项目概要据世界卫生组织称，与年龄相关的晶状体病变是导致视力下降的主要原因白内障（定义为眼睛晶状体混浊）仍然是导致世界范围内白内障的主要原因。世界上的失明是由于晶状体在聚焦过程中改变形状的能力下降引起的。（住宿），进而延伸到老花镜的需要。数十年的研究重点关注先天性晶状体病变，因此，对于促进终生晶状体的潜在细胞和分子机制知之甚少最近的研究报道，EphA2 受体或 ephrin-A5 配体的突变与与人类和小鼠的各种先天性和年龄相关的白内障有关，并且这些双向信号分子是调节晶状体细胞组织和稳定性的关键成分。我们的小鼠模型显示，EphA2 的缺失会导致与人类相似的年龄相关性皮质白内障我们将评估我们的小鼠品系的白内障进展，以研究细胞。我们捕捉到了 EphA2 丢失的结果。周围纤维细胞的细胞骨架结构或细胞间粘附的变化导致光学晶状体皮质的不连续性。我们的新数据表明，该晶状体利用了经典配体介导的 EphA2 双向信号传导和非经典的配体独立 EphA2 信号通路我们采用了经典的 EphA2 信号通路。赤道上皮细胞需要非典型 EphA2 激活，而纤维细胞需要非典型 EphA2 激活分化和成熟，这种受体活性的分离可能解释了我们将评估 EphA2 突变引起的人类先天性和年龄相关性白内障的激活情况。 EphA2 的空间和时间模式并确定已知下游途径的活性我们将EphA2激动剂和拮抗剂肽应用于原代培养小鼠。晶状体上皮细胞产生迷你晶状体作为晶状体发育的体外模型。晶状体中心或核的尺寸和刚度的增加已被认为是不合格的关键因素。不仅与年龄相关的晶状体整体硬度和老花眼的增加，而且还导致营养不良和运输浪费我们新的初步数据表明，EphA2 的缺失会导致年龄相关的核性白内障。我们研究发现 Eph-ephrin 信号传导是正常细胞间粘附和细胞粘附所必需的。驱动核纤维细胞膜重组和压缩的细胞骨架重排。将提供对维持稳态期间协调信号机制的更好理解正常老化以及透明度和生物力学特性发生变化的镜片，这可能会导致开发新的非手术方法来延迟或预防与年龄相关的晶状体病变。