Biomechanical and genetic effects on glaucoma progression

生物力学和遗传对青光眼进展的影响

• 批准号: 10617728
• 负责人: Shin Ae Park
• 金额: $ 16.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617728
• 关键词: 3D ultrasound; Age; Animals; Astrocytes; Atomic Force Microscopy; Autopsy; Axon; Behavior; Biomechanics; Blindness; Cadaver; Canis familiaris; Cell Death; Cell physiology; Cells; Chronic; Clinical; Clinical Data; Collagen; Data; Development; Disease Progression; Disease model; Elastin; Electroretinography; Exhibits; Extracellular Matrix; Eye; Fibroblasts; Genes; Genetic; Glaucoma; Goals; Histologic; Histology; Human; Individual; Individual Differences; Induced Mutation; Ligation; Maps; Matrix Metalloproteinases; Measures; Mechanics; Medical; Mentors; Microfibrils; Missense Mutation; Modeling; Molecular Genetics; Mutation; Neuroglia; Normal Cell; Open-Angle Glaucoma; Operative Surgical Procedures; Optic Disk; Optic Nerve; Optical Coherence Tomography; Papillary; Pathogenicity; Patients; Persons; Physiologic Intraocular Pressure; Predisposition; Property; Publishing; Research; Resistance; Retinal Ganglion Cells; Risk Factors; Role; Sclera; Structure; Testing; Tissues; Trabecular meshwork structure; Translational Research; Vision; Vision Tests; clinically relevant; genetic approach; improved; in vivo; innovation; limbal; multidisciplinary; mutant; nerve damage; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; optic nerve disorder; preservation; pressure; therapeutic target; therapeutically effective; translational study

PROJECT SUMMARY / ABSTRACT Glaucoma is a group of progressive optic neuropathies that together are leading causes of irreversible vision loss. The pathogenic mechanisms that lead to its hallmark, progressive retinal ganglion cell (RGC) death, are unknown, but key risk factors include increased intraocular pressure (IOP). Vision loss often persists with current IOP-lowering treatments, thus urgent needs exist both for better understanding of glaucomatous mechanisms and improved glaucoma therapies other than IOP reduction. Based on our clinical findings that vision is preserved markedly longer in dogs with open-angle glaucoma (OAG) caused by spontaneous mutation of the matrix metalloproteinase-encoding gene ADAMTS10 than in dogs with other forms of glaucoma, and our novel biomechanical findings, I hypothesize that inter-individual differences in biomechanical effects of IOP on optic nerve head (ONH) contribute strongly to glaucoma progression and individuals' differential susceptibilities to it. My long-term goal is to develop novel therapeutic approaches to modify ONH and scleral biomechanics, to permit and improve preservation of optic nerve (ON) and RGC function in glaucoma patients. This multidisciplinary, collaborative translational study will test the central hypothesis that ADAMTS10-mutant individuals have high compliance of ONH, peripapillary sclera, and extracellular matrix (ECM) preceding and during glaucoma development, that protects ON axons even when IOP is chronically elevated. Specific Aims: Using clinically-relevant translational canine chronic glaucoma models, including ADAMTS10-OAG, I propose 3 Aims: In Aim 1, I will test the hypothesis that that ADAMTS10 mutation mitigates IOP-induced ON damage. In Aims 2 and 3, I will test the hypotheses that ONH and peripapillary sclera in eyes with ADAMTS10-OAG (Aim 2: tissue level) and the peripapillary scleral fibroblasts, astrocytes, and lamina cribrosa (LC) cells, and their ECM exhibit more compliant properties (Aim 3: cellular and ECM level). In addition, in Aim 3, I will test if ECM derived from ADAMTS10-mutant LC cells and peripapillary scleral fibroblasts modulates biomechanical properties of non-mutant cells. Significance: Based on extensive preliminary data and using large animal spontaneous glaucoma models, we will provide the first test of the effects of inherently-altered biomechanical properties of peripapillary sclera and ONH, and their potential interactions with elevated IOP, in determining the course of glaucoma progression. Innovation: I will determine 1) novel neuroprotective biomechanical properties of the ONH and peripapillary sclera in glaucoma in `real disease' models, and 2) compliance of astrocytes, LC cells, scleral fibroblasts, and their ECM and cell- ECM interactions in pathogenic mechanisms. My innovation includes our novel, well-established cross- disciplinary collaborative mentoring team with a strong track record in successful translational research in ocular biomechanics and genetics. Overall, findings from this proposal could introduce new and translatable therapeutic targets to preserve ON axons in glaucoma.

项目摘要 /摘要 青光眼是一组进行性视神经病，它们共同引起了不可逆转的视力原因 损失。导致其标志性的渐进视网膜神经节细胞（RGC）死亡的致病机制是 未知，但关键危险因素包括眼内压升（IOP）。视力丧失通常持续存在 当前的降低IOP治疗，因此存在紧急需求以更好地理解青光眼 除IOP还原以外的机制和改善的青光眼疗法。根据我们的临床发现 自发性造成的具有开角青光眼（OAG）的狗的视力明显更长 基质金属蛋白酶编码基因ADAMTS10的突变，与其他形式的狗相比 青光眼和我们新颖的生物力学发现，我假设 IOP对视神经头（ONH）的生物力学作用对青光眼进展有很大贡献 个人对此的不同敏感性。我的长期目标是开发新颖的治疗方法 修改ONH和巩膜生物力学，以允许和改善视神经的保存（ON）和RGC 青光眼患者的功能。这项多学科的协作翻译研究将测试中央 假设Adamts10-突出者对ONH，乳头堆肥和 细胞外基质（ECM）前面和在青光眼发育期间，即使在轴突上也可以保护轴突 IOP长期升高。具体目的：使用临床上的翻译犬慢性青光眼 模型，包括Adamts10-Oag，我提出了3个目标：在AIM 1中，我将测试Adamts10的假设 突变会减轻IOP引起的损伤。在目标2和3中，我将测试Onh和 ADAMTS10-OAG（AIM 2：组织水平）和周围乳头状巩膜成纤维细胞的眼睛中的毛皮巩膜， 星形胶质细胞和椎板纤维片（LC）细胞及其ECM具有更合规的特性（AIM 3：细胞 和ECM级别）。此外，在AIM 3中，我将测试ECM是否从ADAMTS10-突出的LC细胞和 乳腺周围巩膜成纤维细胞调节非突变细胞的生物力学特性。意义：基于 在广泛的初步数据并使用大型动物自发青光眼模型上，我们将提供第一个 测试乳头状巩膜和ONH固有改变的生物力学特性的影响 在确定青光眼进展过程中，潜在与IOP升高的相互作用。创新：我会的 确定1）青光眼中ONH和乳头周围巩膜的新型神经保护性生物力学特性 在“真实疾病”模型中，以及2）星形胶质细胞，LC细胞，硬化成纤维细胞及其ECM和细胞的依从性 致病机制中的ECM相互作用。我的创新包括我们的小说，完善的交叉 - 纪律合作指导团队，在成功的转化研究中具有良好的往绩 眼生物力学和遗传学。总体而言，此提案的发现可能会引入新的且可翻译 在青光眼中保留轴突的治疗靶标。