Primary Cilia of Astrocytes in Glaucoma

青光眼星形胶质细胞的初级纤毛

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要青光眼是一组以视网膜神经节细胞（RGC）损失为特征的神经退行性疾病在美国，它被认为是导致失明的第二大原因，至少有 3 例。如果没有新的治疗方法，到 2030 年，这一数字可能会增加到 420 万人。星形胶质细胞最近作为神经退行性疾病的治疗靶点受到关注。不幸的是，它们变得反应性并在青光眼发病机制中发挥关键作用。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。纤毛是细胞表面基于微管的细胞器，以检测和转导而闻名细胞外信号通过多种信号通路（例如刺猬）调节细胞过程初级纤毛缺陷与许多神经退行性疾病有关。候选人提议研究视神经星形胶质细胞中的纤毛信号传导，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疗法产生重大影响。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防止 RGC 死亡实验性青光眼小鼠模型；2) Sonic Hedgehog信号在RGC视神经星形胶质细胞中的作用总体而言，对星形胶质细胞反应性中纤毛相关的声波刺猬信号传导的研究的见解将是用于开发潜在的青光眼星形胶质细胞靶向治疗方法。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表征基于纤毛的新靶标候选人在原发性纤毛和视网膜疾病方面拥有深厚的背景。建议接受青光眼培训，因为在视觉领域很少研究星形细胞纤毛。 K99阶段，候选人将接受培训，以增加她对神经科学研究和单项研究的理解 PI 将与导师 Yang Sun 和 Yang Hu 博士一起合作。斯坦福大学咨询委员会团队的成员将剖析潜在的分子途径。青光眼视神经病中的反应性星形胶质细胞增生并开发星形胶质细胞靶向疗法神经退行性疾病。