Primary Cilia of Astrocytes in Glaucoma

项目总结/摘要 青光眼是一组以视网膜神经节细胞（RGC）损失为特征的神经变性疾病， 它们的轴突它被描述为美国第二大致盲原因，至少有3 百万人受到影响。如果没有新的治疗方法，到2030年，这一数字可能会上升到420万。 开发星形胶质细胞作为神经退行性疾病的治疗靶点最近受到关注。 它们成为反应性的，并在青光眼发病机制中发挥关键作用。不幸的是， 反应性星形胶质细胞增生的机制及其对视神经病变中RGC轴突的影响仍不清楚。初级 纤毛是细胞表面上基于微管的细胞器，已知用于检测和转导 细胞外信号通过多种信号通路调节细胞过程，如hedgehog 发信号。初级纤毛缺陷与许多神经退行性疾病有关。本工程 候选人提出研究视神经星形胶质细胞中的纤毛信号。更深入地了解星形胶质细胞的作用 可能对开发青光眼的星形胶质细胞靶向疗法具有重要意义。拟议 研究将追求以下目标：1）星形胶质细胞中的初级纤毛是否可以保护RGC免于死亡， 实验性青光眼小鼠模型; 2）在RGC中视神经星形胶质细胞中的sonic hedgehog信号传导的作用 死亡总的来说，从纤毛相关的声音刺猬信号在星形胶质细胞反应性的研究的见解将是 应用于开发潜在的星形胶质细胞靶向治疗青光眼。候选人的总体职业目标是 了解星形胶质细胞导致青光眼的过程，并描述基于纤毛的新靶点 用于神经保护治疗候选人在原发性纤毛和视网膜疾病方面有很深的背景， 建议获得青光眼方面的培训，因为很少在视野中研究星形细胞纤毛。期间 K99阶段，候选人将获得培训，以增加她对神经科学研究的理解， 细胞RNA测序技术。PI将与导师Yang Sun和Yang Hu博士合作， 斯坦福大学顾问委员会的成员。这项提案将剖析潜在的分子途径， 神经胶质瘤视神经病变的反应性星形胶质细胞增生，并开发星形胶质细胞靶向治疗方法， 神经退行性疾病

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.