Investigating mechanosensation in the glaucomatous optic nerve head

项目摘要 本提案的一般目的是为主要研究者（PI）提供经验， 成为一名成功和独立的视觉研究者所需的技能。降低眼内压 (IOP)，青光眼的主要可改变的危险因素和治疗的支柱， 在许多情况下，青光眼的进展。这种差异突出了我们对IOP如何影响的理解上的差距- 诱导的机械应激导致视网膜神经节细胞（RGC）损伤， 青光眼因此，PI的长期目标是开发一个独立的研究计划， 研究RGC及其细胞和结构支持系统响应的机制 机械压力源这些研究将为开发新的治疗方法奠定基础， 无论IOP如何，都有可能预防RGC死亡。 该领域的共识是RGC损伤的初始部位发生在视神经乳头（ONH）。的 在ONH的细胞中，星形胶质细胞是这些机械应激源的最可能的传感器。总理候选人 星形胶质细胞感受和响应机械刺激的通道是机械敏感通道。在目标1中， 我们将检验星形胶质细胞是ONH中关键的机械感受器的假设， 周围硬度和机械应变的变化转化为ECM完整性和组织的改变 硬化在目的2中，我们将检验抑制ONH星形胶质细胞压电机械敏感性的假设， 通道活性将防止IOP诱导的星形胶质细胞反应性和RGC死亡。我们将结合使用 组织工程技术、生物力学工具和体内青光眼模型，以实现我们的具体目标。 目标。通过指导方法分析青光眼中ONH星形胶质细胞的机械感觉， 在星形胶质细胞/基质生物学，机械生物学，组织工程， 和青光眼模型系统，PI将独特地定位自己，以确定这种新的药物靶点。的 拟议的研究和职业发展计划的成功是由特殊的多层次加强 在SUNY UMU视觉研究中心的指导环境，参与锡拉丘兹 锡拉丘兹大学的生物材料研究所，最先进的设施和强大的合作研究 社区

Project Summary The general purpose of this proposal is to provide the principle investigator (PI) with the experience and skills necessary to become a successful and independent vision researcher. Lowering intraocular pressure (IOP), the primary modifiable risk factor for glaucoma and the mainstay of treatment, does not halt the progression of glaucoma in many cases. This discrepancy highlights gaps in our understanding of how IOP- induced mechanical stressors cause damage to retinal ganglion cells (RGCs), the major cell type affected in glaucoma. Thus, the PI’s long-term goal is to develop an independent research program dedicated to investigating mechanisms by which RGCs and their cellular and structural support system respond to mechanical stressors. These studies will set the stage for the development of new treatments, with the potential to prevent RGC death regardless of IOP. The consensus in the field is that the initial site of RGC injury occurs at the optic nerve head (ONH). Of the cells of the ONH, astrocytes are the most likely sensors of these mechanical stressors. A prime candidate through which astrocytes sense and respond to mechanical stimuli is mechanosensitive channels. In Aim 1, we will test the hypothesis that astrocytes are key mechanosensors within the ONH, and that they translate changes in surrounding stiffness and mechanical strain into alterations in ECM integrity and tissue stiffening. In Aim 2, we will test the hypothesis that inhibition of ONH astrocyte Piezo mechanosensitive channel activity will prevent IOP-induced astrocyte reactivity and RGC death. We will use a combination of tissue engineering techniques, biomechanical tools, and in vivo glaucoma models to accomplish our specific aims. By analyzing ONH astrocyte mechanosensation in glaucoma through a mentored approach, and by acquiring a solid foundation in the fields of astrocyte/matrix biology, mechanobiology, tissue engineering, and glaucoma model systems, the PI will uniquely position herself to identify such novel drug targets. The success of the proposed research and career development plan is reinforced by the exceptional multi-tiered mentoring environment at the Center for Vision Research at SUNY UMU, participation in the Syracuse Biomaterials Institute at Syracuse University, state-of-the-art facilities, and a strongly collaborative research community.