Targeting Tissue Biomechanics for Treatment of Glaucoma

青光眼是由于视网膜神经节细胞变性而导致不可逆失明的主要原因 （RGC）及其轴突。视神经乳头（ONH）的生物力学稳定性， 筛板（LC）和乳头周围巩膜（PPS），并富含弹性纤维，已被假定发挥作用， 在维持RGC轴突的正常功能中起重要作用。在我们的上一个赠款周期，源于我们的 在微纤维相关基因ADAMTS 10中发现了一个引起结肠癌的突变，我们将重点放在 微纤维，并确定其在青光眼发病机制中的重要作用。微纤维主要由 的纤维蛋白-1（由FBN 1编码），并且是适当的弹性纤维组装所需的，有助于它们的 生物力学性能弹性蛋白通过赖氨酰氧化酶样1（由LOXL 1编码）进行交联， 另一个关键因素，为适当的弹性纤维的形成。缺乏LOXL 1（Loxl 1-/-）的小鼠发育出骨盆底器官 由于弹性纤维畸形导致的脱垂（POP），证明了LOXL 1在正常组织中的重要作用。 弹性纤维形成。我们对Loxl 1-/-小鼠的初步数据显示了眼部病理学，包括 通过原子力显微镜（AFM）和超微结构变化确定的异常生物力学， PPS中的胶原蛋白和弹性纤维。一项具有里程碑意义的研究发现，LOXL 1基因组 由剥脱综合征（XFS）引起的剥脱性青光眼（XFG）变体， 弹性纤维缺陷的全身表现，包括POP的更高患病率。 与XFG/XFS已经复制在许多人群中，然而，它也被认为是有缺陷的， LOXL 1是必需的，它不足以引起疾病，这表明必须涉及其他因素。我们 假设微纤维是一个关键的额外因素，部分原因是它们在适当的 形成弹性纤维。我们的中心假设是，在生物力学和结构的改变， 由弹性纤维缺陷引起的ONH导致RGC轴突病变。这一假设直接表明， 靶向生物力学异常可能被证明是青光眼患者的有效新治疗。到 为了验证我们的假设，我们将使用我们新创建的双突变体（Fbn 1C 1039 G/+/Loxl 1-/-）和Loxl 1-/-小鼠， 研究SA 1弹性纤维缺陷引起的生物力学和超微结构变化， 这些变化对SA 2中与青光眼相关的RGC轴突病理学的影响。根据调查结果，我们 将测试靶向生物力学异常对保护RGC轴突病理的有效性。 这项研究的成功将为ONH的生物力学作用提供机理上的见解， 更重要的是，它将为青光眼带来急需的新治疗方法 患者

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.