Biomechanical and genetic effects on glaucoma progression

项目总结/摘要 青光眼是一组进行性视神经病变，是导致视力不可逆的主要原因 损失导致其标志性进行性视网膜神经节细胞（RGC）死亡的致病机制是 未知，但关键风险因素包括眼内压（IOP）升高。视力丧失通常持续存在， 目前降低IOP的治疗，因此迫切需要更好地了解青光眼 机制和改善青光眼治疗，而不是降低IOP。根据我们的临床发现， 自发性青光眼引起的开角型青光眼（OAG）的狗的视力保留时间明显更长， 突变的基质金属蛋白酶编码基因ADAMTS 10比在狗与其他形式的 青光眼和我们新的生物力学研究结果，我假设， IOP对视神经乳头（ONH）的生物力学影响强烈地促进青光眼进展， 我的长期目标是开发新的治疗方法， 改良ONH和巩膜生物力学，以允许和改善视神经（ON）和RGC的保留 在青光眼患者中的作用。这种多学科的，合作的翻译研究将测试中央 假设ADAMTS 10-突变个体具有高的ONH、视乳头周围巩膜顺应性， 细胞外基质（ECM）之前和青光眼发展过程中，保护ON轴突，即使 IOP长期升高。具体目的：使用临床相关的转化犬慢性青光眼 模型，包括ADAMTS 10-OAG，我提出了3个目标：在目标1中，我将测试假设，ADAMTS 10 突变减轻了IOP诱导的ON损伤。在目标2和3中，我将检验ONH和 用ADAMTS 10-OAG的眼睛中的视乳头周围巩膜（Aim 2：组织水平）和视乳头周围巩膜成纤维细胞， 星形胶质细胞和筛板（LC）细胞，以及它们的ECM表现出更柔顺的性质（目的3：细胞 ECM水平）。此外，在目标3中，我将测试ECM是否来源于ADAMTS 10突变型LC细胞， 视乳头周围巩膜成纤维细胞调节非突变细胞的生物力学性质。重要性：基于 基于广泛的初步数据，并使用大型动物自发性青光眼模型，我们将提供第一个 测试视乳头周围巩膜和ONH的固有改变的生物力学特性的影响，以及它们的 与IOP升高的潜在相互作用，以确定青光眼进展的过程。创新：我会 确定1）青光眼中ONH和视乳头周围巩膜的新的神经保护生物力学特性 在“真实的疾病”模型中，和2）星形胶质细胞、LC细胞、巩膜成纤维细胞及其ECM和细胞- ECM在致病机制中的相互作用我的创新包括我们新颖的，成熟的交叉- 学科协作指导团队，在成功的翻译研究方面有着良好的记录， 眼部生物力学和遗传学。总的来说，这项建议的结果可以引入新的和可翻译的 治疗靶点，以保护青光眼中的ON轴突。

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.