Novel ocular imaging and molecular analysis of anterior eye segment for glaucoma

青光眼眼前节的新型眼部成像和分子分析

• 批准号: 10607885
• 负责人: Tsutomu Kume
• 金额: $ 67.78万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607885
• 关键词: Adrenal Cortex Hormones; Affect; Anatomy; Angiopoietins; Animals; Anterior eyeball segment structure; Aqueous Humor; Area; Blindness; Blood Vessels; Cardiac; Cells; Characteristics; Circulation; Data; Detection; Development; Disease; Drainage procedure; Electron Microscopy; Endothelial Cells; Evaluation; Extracellular Matrix; Eye diseases; FOXC2 gene; Family; Gene Expression; Glaucoma; Goals; Height; Histologic; Human; Image; Imaging Techniques; Imaging technology; Immunohistochemistry; Impairment; Lighting; Limb structure; Lymph; Lymphatic; Lymphedema; Maintenance; Measurement; Measures; Mediating; Mesenchymal; Methodology; Methods; Mission; Molecular; Molecular Analysis; Morphology; Mus; Mutant Strains Mice; Mutation; Neural Crest; Ocular Hypertension; Optic Nerve; Optical Coherence Tomography; Pathologic; Pathway interactions; Patients; Phase; Physiologic Intraocular Pressure; Play; Public Health; Research; Resistance; Resolution; Retina; Risk Factors; Role; Scanning; Signal Pathway; Speed; Structure; Structure of sinus venosus of sclera; System; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissues; Trabecular meshwork structure; Variant; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-3; Vascular System; Veins; Visible Radiation; Vision; Visual impairment; Width; Wild Type Mouse; age related; aqueous; dominant genetic mutation; early onset; experimental study; improved; in vivo; member; meter; modifiable risk; mutant; nano; nerve damage; novel; novel diagnostics; ocular imaging; older patient; optic nerve disorder; pressure; primary congenital glaucoma; single-cell RNA sequencing; therapeutically effective; transcription factor

Project Summary Glaucoma is the leading cause of irreversible blindness worldwide and is a heterogeneous group of ocular diseases characterized by optic nerve damage and impaired vision. The majority of glaucoma patients are elderly due to the age-related, optic nerve disease, whereas there are early-onset forms of glaucoma: primary congenital glaucoma and developmental glaucoma. The resistance to drainage of aqueous humor from the anterior segment of the eye into the systemic circulation leads to the elevation of intraocular pressure (IOP), and elevated IOP is the primary and only modifiable risk factor for glaucoma. Despite the current treatment options aimed at lowering IOP, there are urgent needs to develop new, more effective therapeutic approaches. Aqueous humor drainage as the conventional outflow pathway is mediated through the trabecular meshwork (TM), which is derived from the neural crest (NC) lineage, into a specialized, lymphatic-like vessel known as Schlemm's canal (SC). Recent evidence indicates that SC has specialized and unique vascular endothelial cells (ECs) and that the signaling pathways such as Angiopoietin/Tie2 are essential for the formation and maintenance of SC vasculature. The long-term goal of our group is to elucidate the fundamental mechanisms that regulate SC maintenance/function and to understand how disruption of these mechanisms leads to impaired outflow causing increased IOP in pathological settings. To image the full-circle SC and evaluate TM stiffness in mice, our group has recently developed a circular-scanning visible-light OCT (vis-OCT) system. FOXC2 is a member of the FOX (Forkhead box) transcription factor family and has critical roles in vascular development and disease. Inactivating mutations in human FOXC2 are dominantly associated with lymphedema, which is characterized by obstructed lymph drainage in the limbs, and recent evidence has shown that FOXC2 variants possess a role as putative modifiers for the development of primary congenital glaucoma. However, its role in TM and SC cells has yet to be fully investigated. The results from our preliminary experiments via vis-OCT imaging, immunohistochemistry, and single-cell RNA sequencing indicate that the NC-Foxc2-/- mutation is associated with defective TM formation, abnormal SC morphology, or the absence of the SC, a reduction in expression of PROX1, VEGFR3, and TEK in SC ECs, and elevated IOP, and that the EC-Foxc2-/- mutation results in impaired SC formation. Our central hypothesis is that novel diagnostic vis-OCT imaging techniques elucidate the significance of Foxc2 function in both NC-derived TM cells and SC ECs in SC formation/maintenance and TM stiffness. To test this hypothesis, we have two Specific Aims. First, we will develop a new balanced-detection vis-OCT to determine the anatomical influence of the Foxc2 regulatory network in SC formation/maintenance. Second, we will develop new methodologies to evaluate TM stiffness based on vis-OCT phase imaging after high-speed temporal speckle reduction to define the functional influence of the Foxc2 regulatory network in TM stiffness and ECM compositions.

项目总结