Primary Cilia of Astrocytes in Glaucoma

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Project Summary/Abstract Glaucoma is a group of neurodegenerative diseases marked by the loss of retinal ganglion cells (RGCs) and their axons. It is characterized as the second leading cause of blindness in the United States with at least 3 million people affected. This number is likely to rise to 4.2 million by 2030 if no new therapeutics can be developed. Astrocytes are recently gaining attention as therapeutic targets for neurodegeneration diseases. They become reactive and play critical roles in glaucoma pathogenesis. Unfortunately, the underlying mechanisms of reactive astrogliosis and its impact on RGC axons in optic neuropathies remain unclear. Primary cilia are microtubule-based organelles on the cell surface that are known for detecting and transducing extracellular cues to regulate cellular processes through a variety of signaling pathways such as hedgehog signaling. Defective primary cilia are associated with numerous neurodegenerative diseases. In this project, the candidate proposes to study cilia signaling in optic nerve astrocytes. A deeper understanding of astrocytes' role could have significant implications for developing astrocyte-targeting therapeutics for glaucoma. The proposed study will pursue the following aims: 1) whether primary cilia in astrocytes protect against RGC death in experimental glaucoma mouse models; 2) the role of sonic hedgehog signaling in optic nerve astrocytes in RGC death. Overall, insights from the study of cilia-associated sonic hedgehog signaling in astrocyte reactivity will be applied to develop potential astrocyte-targeting treatments for glaucoma. The candidate’s overall career goal is to understand the process of astrocytes that contribute to glaucoma and to characterize novel cilia-based targets for neuroprotective treatments. The candidate has a deep background in primary cilia and retinal diseases and proposes to obtain training in glaucoma because astrocytic cilia is rarely studied in the vision field. During the K99 phase, the candidate will obtain training to increase her understanding of neuroscience research and single- cell RNA sequencing technique. The PI will work with mentors Drs. Yang Sun and Yang Hu, together with members of a Stanford advisory committee team. This proposal will dissect the molecular pathways underlying reactive astrogliosis in glaucomatous optic neuropathies and develop astrocyte-targeting therapeutics for neurodegenerative diseases.