Investigating mechanosensation in the glaucomatous optic nerve head

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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.