Primary Cilia of Astrocytes in Glaucoma

青光眼星形胶质细胞的初级纤毛

• 批准号: 10644528
• 负责人: Ke Veronica Ning
• 金额: $ 12.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644528
• 关键词: Ablation; Acceleration; Address; Advisory Committees; Affect; Astrocytes; Attention; Attenuated; Axon; Blindness; Calcium; Cell Count; Cell Death; Cell Survival; Cell membrane; Cell physiology; Cell surface; Cilia; Cilium Microtubule; Coupled; Cues; Data; Disease; Elderly; Exhibits; Glaucoma; Glial Fibrillary Acidic Protein; Goals; Heterogeneity; Human; Image; Inflammatory; Injections; Injury; Intraperitoneal Injections; Knockout Mice; Length; LoxP-flanked allele; Membrane; Mentors; Methods; Modeling; Molecular; Mus; Nerve Crush; Nerve Degeneration; Neurodegenerative Disorders; Neurosciences Research; Ocular Hypertension; Optic Disk; Optic Nerve; Organelles; Pathogenesis; Pathologic; Pathway interactions; Pattern; Persons; Phase; Physiologic Intraocular Pressure; Play; Process; Proteins; RNA; Recovery of Function; Research; Retina; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; SHH gene; Sampling; Sensory; Signal Pathway; Signal Transduction; Silicone Oils; Tamoxifen; Techniques; Training; Transgenic Mice; United States; Viral; Vision; Work; aged; astrogliosis; axon injury; axon regeneration; career; extracellular; glial activation; high risk; in vivo; insight; member; mouse model; myelination; nerve damage; neuroprotection; novel; novel therapeutics; optic nerve disorder; overexpression; programs; receptor; response; single-cell RNA sequencing; smoothened signaling pathway; targeted treatment; therapeutic target; transcriptome

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.

项目摘要/摘要 青光眼是一组神经退行性疾病，以视网膜神经节细胞(RGC)丢失和 他们的轴突。它被认为是美国第二大致盲原因，至少有3 受影响的人数达百万。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 发展起来的。近年来，星形胶质细胞作为神经退行性疾病的治疗靶点受到了越来越多的关注。 它们成为反应性的，并在青光眼的发病机制中发挥关键作用。不幸的是，潜在的 反应性星形胶质细胞增生症的机制及其对视神经病变中RGC轴突的影响尚不清楚。主要 纤毛是细胞表面以微管为基础的细胞器，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，如刺猬 发信号。初级纤毛缺陷与许多神经退行性疾病有关。在这个项目中， 候选人建议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 可能对开发针对青光眼的星形胶质细胞靶向疗法具有重要意义。建议数 研究将追求以下目标：1)星形胶质细胞的初级纤毛是否对RGC死亡有保护作用 实验性青光眼小鼠模型；2)视神经星形胶质细胞中声波刺激物信号在RGC中的作用 死亡。总体而言，纤毛相关的声波刺猬信号在星形胶质细胞反应性中的研究将带来以下启示 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 了解导致青光眼的星形胶质细胞的过程，并表征基于纤毛的新靶点。 进行神经保护治疗。候选人在原发纤毛和视网膜疾病方面有深厚的背景， 建议接受青光眼训练，因为在视野中对星形细胞纤毛的研究很少。在.期间 K99阶段，应聘者将接受培训，以增加她对神经科学研究的理解和单项- 细胞RNA测序技术。国际和平协会将与导师杨孙博士和杨虎博士合作，以及 斯坦福大学顾问委员会团队的成员。这项提议将剖析潜在的分子途径 青光眼视神经病变中的反应性星形胶质细胞增生症及其星形胶质细胞靶向治疗 神经退行性疾病。