Receptor tyrosine kinase signaling in astrocyte migration and angiogenesis

星形胶质细胞迁移和血管生成中的受体酪氨酸激酶信号传导

• 批准号: 10734124
• 负责人: Chenqi Tao
• 金额: $ 41.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734124
• 关键词: Ablation; Actins; Adaptor Signaling Protein; Angiogenic Factor; Astrocytes; Behavior; Binding; Blood Vessels; Blood-Retinal Barrier; Coloboma; Data; Development; Disease; Endothelial Cells; Endothelium; Eye Development; Eye diseases; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Genes; Genetic; Glaucoma; Gliosis; Goals; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Health; Homeostasis; Image; Impairment; Invaded; Knock-out; Ligands; MAP Kinase Gene; Maintenance; Mediating; Molecular; Mutant Strains Mice; Neonatal; Nervous System; Nuclear; Orphan; PIK3CG gene; Pathway interactions; Physiology; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Polymers; Receptor Protein-Tyrosine Kinases; Retina; Retinal Ganglion Cells; Retinopathy of Prematurity; Role; Signal Pathway; Signal Transduction; Source; Testing; Tissues; Vascularization; angiogenesis; autocrine; cell motility; cohort; migration; mouse model; mutant; neural; paracrine; polymerization; recruit; rho; scaffold; single-cell RNA sequencing; transcription factor; transcriptomics; transmission process

PROJECT SUMMARY Retinal astrocytes form the integral part of the neural-glial-vascular network in the retina. They contribute to the establishment of the retinal vasculature, maintenance of the blood-retina barrier and health of retinal ganglion cells. Although several signaling pathways are known to be active in astrocytes, how they are integrated to regulate astrocyte development and physiology is still poorly understood. This project will investigate the role and mechanism of PDGF and FGF signaling, two closely related receptor tyrosine kinase pathways, in astrocyte development. By generating mouse mutants and performing living imaging, we will delineate the PDGF signaling cascade specific to astrocytes and understand how it regulates the migratory behaviors of astrocytes. Furthermore, we will investigate the molecular mechanism of FGF signaling in regulating astrocyte maturation. Lastly, we will test the hypothesis that FGF and PDGF signaling are required for suppression of astrocyte maturation and induction of angiogenesis. Astrocytic malfunction can lead to impaired retinal vascularization, breakdown of the blood-retinal-barrier and reactive gliosis, contributing to a cohort of blinding diseases such as retinopathy of prematurity (ROP), coloboma, and glaucoma. This project is expected to illuminate the mechanism of PDGF and FGF signaling in astrocytes, which will contribute to understanding and treatment of ocular diseases.

项目摘要 视网膜星形胶质细胞形成视网膜中神经胶质血管网络的组成部分。他们 有助于建立视网膜血管系统，维持血-视网膜屏障 和视网膜神经节细胞的健康。尽管已知有几种信号通路是活跃的， 在星形胶质细胞中，它们如何整合以调节星形胶质细胞的发育和生理仍然是未知的。 不太了解。本课题旨在探讨PDGF和FGF在肿瘤发生发展中的作用及其机制 信号，两个密切相关的受体酪氨酸激酶途径，在星形胶质细胞的发展。通过 产生小鼠突变体并进行活体成像，我们将描述PDGF信号转导 特定于星形胶质细胞的级联反应，并了解它如何调节星形胶质细胞的迁移行为。 星形胶质细胞此外，我们将研究FGF信号转导的分子机制， 调节星形胶质细胞成熟。最后，我们将检验FGF和PDGF信号转导 是抑制星形胶质细胞成熟和诱导血管生成所必需的。星形细胞 功能障碍可导致视网膜血管化受损、血视网膜屏障破坏 和反应性神经胶质增生，导致一组致盲性疾病，如视网膜病变， 早产（ROP）、缺损和青光眼。该项目预计将照亮 星形胶质细胞中PDGF和FGF信号传导的机制，这将有助于理解和 治疗眼部疾病。