Investigating mechanosensation in the glaucomatous optic nerve head

项目摘要 这项建议的一般目的是向首席调查员(PI)提供经验和 成为一名成功和独立的视力研究人员所需的技能。降低眼压 (IOP)是青光眼的主要可改变的危险因素，也是治疗的主要手段，但并不能阻止 在许多情况下青光眼的进展。这一差异突显了我们对眼压如何- 诱导的机械应激会对视网膜神经节细胞(RGC)造成损害，RGC是受影响的主要细胞类型 青光眼。因此，国际和平研究所的长期目标是制定一个独立的研究计划，致力于 研究视网膜节细胞及其细胞和结构支持系统的反应机制 机械应激源。这些研究将为开发新的治疗方法奠定基础， 无论眼压如何，都有可能防止RGC死亡。 该领域的共识是RGC损伤的最初位置发生在视神经头(ONH)。中的 ONH的细胞、星形胶质细胞是这些机械应激源最有可能的传感器。一位主要候选人 星形胶质细胞感知机械刺激并对机械刺激作出反应的通道是机械敏感通道。在目标1中， 我们将测试星形胶质细胞是ONH中的关键机械传感器的假设，以及它们翻译 周围硬度和机械应变的变化导致ECM完整性和组织的变化 变得僵硬。在目标2中，我们将检验对ONH星形胶质细胞Piezo的抑制具有机械敏感性的假设 通道活性可防止眼压引起的星形胶质细胞反应和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 目标。通过一种有指导的方法分析青光眼中ONH星形胶质细胞的机械感觉，并通过 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将独特地定位自己来识别这些新的药物靶点。这个 拟议的研究和职业发展计划的成功得到了特殊的多层次 纽约州立大学密歇根州立大学视觉研究中心的指导环境，参与锡拉丘兹 锡拉丘兹大学生物材料研究所，最先进的设施，以及强有力的合作研究 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.