Eph-ephrin signaling in the lens

晶状体中的肝配蛋白信号传导

• 批准号: 10095178
• 负责人: Catherine Kehsin Cheng
• 金额: $ 45.67万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 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/10095178
• 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; Goals; Growth; Homeostasis; Human; Immunofluorescence Immunologic; In Vitro; Knock-out; Lead; Lens Opacities; Lens development; Life; Ligand Binding; Ligands; Link; Maps; Mass Spectrum Analysis; Measures; Mediating; Microscopy; 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; Resolution; Role; Serine; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Tissues; Tyrosine; Vision; Visual impairment; Work; World Health Organization; age related; epithelial to mesenchymal transition; fiber cell; in vitro Model; lens; lens cortex; lens transparency; mouse model; normal aging; prevent; receptor; segregation; wasting

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.

项目总结