Targeting Tissue Biomechanics for Treatment of Glaucoma

靶向组织生物力学治疗青光眼

• 批准号: 10468899
• 负责人: Rachel W Kuchtey
• 金额: $ 44.33万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468899
• 关键词: Alleles; Angiotensin II; Animal Model; Aorta; Aortic Aneurysm; Atomic Force Microscopy; Axon; Axonal Transport; Biomechanics; Biometry; Blindness; Clinical; Collagen; Collagen Fiber; Cornea; Data; Defect; Development; Disease; Elastic Fiber; Elastin; Elderly; Elements; Etiology; Exfoliation Syndrome; Exhibits; Extracellular Matrix; Eye; FBN1; Genes; Glaucoma; Grant; High Prevalence; Histology; Human; Immunohistochemistry; Intervention; Investigation; Lead; Link; Longevity; Marfan Syndrome; Measures; Microfibrils; Microscopy; Monitor; Mus; Mutant Strains Mice; Mutation; Ocular Pathology; Optic Disk; Optic Nerve; Organ; Pathogenesis; Pathology; Patients; Pelvic floor structure; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; Property; Protein-Lysine 6-Oxidase; Ptosis; Publishing; Retinal Ganglion Cells; Risk; Role; Sclera; Structure; Testing; Therapeutic Intervention; Thinness; Time; TimeLine; Tissues; Treatment Efficacy; base; crosslink; effectiveness testing; genetic variant; genipin; insight; malformation; mouse model; mutant; nerve damage; neuroprotection; novel; novel strategies; novel therapeutic intervention; null mutation; prevent; receptor; retinal ganglion cell degeneration; scaffold; stem; success; targeted agent; transmission process

Glaucoma is the leading cause of irreversible blindness that is due to degeneration of retinal ganglion cells (RGCs) and their axons. Biomechanical stability of the optic nerve head (ONH) which is composed of the lamina cribrosa (LC) and peripapillary sclera (PPS) and is rich in elastic fibers, has been postulated to play an important role in maintaining normal function of RGC axons. In our previous grant cycle, stemming from our initial discovery of a glaucoma-causing mutation in a microfibril-related gene, ADAMTS10, we focused on microfibrils and established their important role in glaucoma pathogenesis. Microfibrils are primarily composed of fibrillin-1 (encoded by FBN1) and required for proper elastic fiber assembly, contributing to their biomechanical properties. Elastin undergoes crosslinking by Lysyl Oxidase Like 1 (encoded by LOXL1), another key element for proper elastic fiber formation. Mice lacking LOXL1 (Loxl1-/-) develop pelvic floor organ prolapse (POP) due to malformation of elastic fibers, demonstrating the essential role of LOXL1 in normal elastic fiber formation. Our preliminary data with Loxl1-/- mice demonstrated ocular pathologies, including abnormal biomechanics as determined by Atomic Force Microscopy (AFM) and ultrastructural changes of collagens and elastic fibers in the PPS. A landmark study discovered the association of LOXL1 genomic variants with exfoliation glaucoma (XFG) caused by exfoliation syndrome (XFS) which is a disease with systemic manifestations of elastic fiber defects, including higher prevalence of POP. The association of LOXL1 with XFG/XFS has been replicated in many populations, however, it is also recognized that while defective LOXL1 is necessary, it is not sufficient to cause disease, suggesting that other factors must be involved. We hypothesize that microfibrils are a key additional factor, in part because of their indispensable role for proper formation of elastic fibers. Our central hypothesis is that alterations in the biomechanics and structure of the ONH caused by defective elastic fibers result in RGC axon pathology. This hypothesis suggests that directly targeting biomechanical abnormalities may prove to be an effective novel treatment for glaucoma patients. To test our hypotheses, we will use our newly created double mutant (Fbn1C1039G/+/Loxl1-/-) and Loxl1-/- mice to investigate biomechanical and ultrastructural changes caused by elastic fiber defects in SA 1 and to determine the effect of these changes on RGC axon pathology relevant to glaucoma in SA 2. Based on the findings, we will test the effectiveness of targeting biomechanical abnormalities for protection against RGC axon pathology. Success of this investigation would provide mechanistic insight into the role of biomechanics of the ONH in glaucoma and, more importantly, it would lead to a much-needed novel treatment approach for glaucoma patients.

青光眼是由于视网膜神经节细胞变性而导致的不可逆性失明的主要原因 (RGC)及其轴突。视神经头的生物力学稳定性 筛板(LC)和乳头状巩膜周围(PPS)富含弹性纤维，被认为是一种 对维持RGC轴突的正常功能具有重要作用。在我们之前的赠款周期中，源于我们的 我们关注的是微纤维相关基因ADAMTS10中导致青光眼的突变的初步发现 并确定了它们在青光眼发病机制中的重要作用。微原纤维主要由 纤维蛋白-1(由FBN1编码)，是正常弹性纤维组装所必需的，有助于它们的 生物力学特性。弹性蛋白通过Lysyl Oxidase like 1(由LOXL1编码)进行交联， 形成适当弹性纤维的另一个关键因素。缺乏LOXL1(LoxL1-/-)的小鼠发育为盆底器官 由弹性纤维畸形引起的脱垂(POP)，表明LOXL1在正常人群中起重要作用 弹性纤维的形成。我们在Loxl1/-小鼠身上的初步数据显示了眼睛的病理，包括 应用原子力显微镜(AFM)检测关节盘异常生物力学及超微结构改变 PPS中的胶原蛋白和弹性纤维。一项里程碑式的研究发现LOXL1基因组与 由剥脱综合征(XFS)引起的剥脱性青光眼(XFG)的变异体 弹力纤维缺陷的全身性表现，包括POP患病率较高。LOXL1的关联性 然而，随着XFG/XFS已经在许多人群中复制，人们也认识到，尽管有缺陷 LOXL1是必需的，但不足以致病，提示一定有其他因素参与。我们 假设微原纤维是一个关键的附加因素，部分原因是它们对适当的 弹性纤维的形成。我们的中心假设是关节突关节的生物力学和结构的改变 弹性纤维缺陷引起的ONH导致RGC轴突病理改变。这一假说直接表明 靶向生物力学异常可能被证明是治疗青光眼患者的一种有效的新方法。至 测试我们的假设，我们将使用我们新创建的双重突变体(Fbn1C1039G/+/Loxl1-/-)和Loxl1-/-小鼠来 探讨弹力纤维缺陷对SA-1的生物力学和超微结构的影响 这些变化对与SA-2青光眼相关的RGC轴突病理的影响。 将测试靶向生物力学异常以保护RGC轴突病理的有效性。 这项研究的成功将提供对ONH生物力学在ONH中的作用的机械性见解 青光眼，更重要的是，它将导致一种急需的青光眼新治疗方法 病人。