Signaling networks and transcriptional programs in lens vesicle formation

晶状体囊泡形成中的信号网络和转录程序

• 批准号: 10621311
• 负责人: Qian Wang
• 金额: $ 11.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621311
• 关键词: Ablation; Adaptor Signaling Protein; Adherence; Adherens Junction; Affect; Anterior; Anterior eyeball segment structure; Anterior segment dysgenesis; Cell Adhesion Molecules; Cell model; Cells; Ciliary Body; Complex; Cornea; Data; Defect; Development; Disease; Ectoderm; Ectoderm Cell; Environment; Epithelial Cells; Epithelium; Event; Eye; Eye Abnormalities; Eye Development; Eye diseases; FRAP1 gene; Fibroblast Growth Factor; Genes; Genetic; Genetic Transcription; Glaucoma; Goals; Human; Irido-corneo-trabecular dysgenesis; Iris; Knockout Mice; Lens development; Link; MAP Kinase Gene; Mediating; Medical center; Mentors; Molecular Target; Mus; Names; PIK3CG gene; Pathogenesis; Pattern; Phase; Phenotype; Preventive; Preventive Medicine; Regulation; Regulatory Pathway; Research; Research Personnel; Resources; Risk; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Transcriptional Regulation; Universities; Vesicle; Visual impairment; WNT Signaling Pathway; career development; conditional knockout; disorder prevention; effective intervention; gain of function; gene regulatory network; innovation; lens; loss of function; mouse model; mutant; novel; programs; single-cell RNA sequencing; transcription factor

PROJECT SUMMARY /ABSTRACT Anterior segment dysgenesis (ASD) refers to a spectrum of disorders that affect the front of the eye, including the corneal, iris/ciliary body, and lens. Among the characterized ASD genes, the majority encode transcription factors. However, the upstream signaling events that control these transcription factors are unclear. My long- term goal is to establish the gene regulatory networks that underlies the development of the anterior segment of the eye, in order to identify molecular targets for disease prevention and treatment. The objective of this proposal is to study signaling networks and transcriptional programs in lens development. In particular, I have identified mechanistic target of rapamycin complex 1 (mTORC1) signaling as a novel regulator in lens vesicle formation. And I propose to investigate both the upstream regulators and the downstream targets of mTORC1, using a combination of conditional knockout mouse and primary lens epithelium cell models. My central hypothesis is that Fibroblast Growth Factor (FGF) signaling activates mTORC1 in the lens epithelium (Aim 1), and this mTORC1 signaling controls cell adherence during lens vesicle formation through regulating Wnt signaling (Aim 2). In Aim 1, I will elucidate the mechanism underlying how FGF signaling activates mTORC1 in the lens epithelium. In Aim 2, I will investigate how mTORC1 regulates Wnt signaling and the functional significance of mTORC1-Wnt axis in the formation of adherens junctions in the lens epithelium. In addition, I propose to identify mTORC1 mediated transcriptional programs during lens vesicle formation by Single-cell RNA-sequencing. This proposal is innovative because it identifies a novel regulatory pathway in lens vesicle development. It also links signaling pathways and transcriptional factors to elucidate the mechanism of lens vesicle development and disease pathogenesis. Results from this study are significant in that they are expected to impact the understanding of normal and defective development of the lens vesicle, and have the potential to reveal novel molecular targets for preventive purpose of disease caused by congenital lens defects. The mentored phase of this project will be conducted under the guidance of Drs. Xin Zhang and Carol Mason (Columbia University Irving Medical Center), who are experts in eye development and signaling pathways. Additional advice will be obtained from my scientific advisor Dr. Melinda Duncan and Dr. Peter Sims on aspect of lens development and Single cell RNA-sequencing, respectively. Resources for career development along with the research environment at Columbia University are ideal for my transition into an independent investigator studying signaling mechanisms of eye development and disease.

项目摘要 /摘要 前部段失去障碍（ASD）是指影响眼前的一系列疾病，包括 角膜，虹膜/睫状体和镜头。在特征的ASD基因中，大多数编码转录 因素。但是，控制这些转录因子的上游信号事件尚不清楚。我的长期 术语目标是建立基因调节网络，该网络是基于前部发展的基础 眼睛，以识别用于预防疾病和治疗的分子靶标。该提议的目的 是研究晶状体开发中的信号网络和转录程序。特别是，我已经确定 雷帕霉素复合物1（MTORC1）信号传导的机械靶标是晶状体形成中的新调节剂。 我建议使用A 条件基因敲除小鼠和原代晶状体上皮细胞模型的组合。我的中心假设是 该成纤维细胞生长因子（FGF）信号传导激活镜头上皮中的mtorc1（aim 1），这 MTORC1信号通过调节Wnt信号来控制晶状体囊泡形成过程中的细胞粘附（AIM 2）。在AIM 1中，我将阐明FGF信号传导如何激活MTORC1的机制 上皮。在AIM 2中，我将研究MTORC1如何调节Wnt信号传导和功能意义 MTORC1-WNT轴形成在晶状体上皮中的粘附连接处。此外，我建议确定 MTORC1通过单细胞RNA测序在晶状体囊泡形成过程中介导的转录程序。这 提案具有创新性，因为它确定了晶状体发育中的新调节途径。它也链接 信号通路和转录因子，以阐明晶状体发育机制和 疾病发病机理。这项研究的结果很大，因为它们有望影响 了解晶状体囊泡的正常和有缺陷的发展，并具有揭示新颖的潜力 先天性晶状体缺陷引起的疾病的预防目的的分子靶标。 该项目的指导阶段将在DRS的指导下进行。 Xin Zhang和Carol Mason （哥伦比亚大学欧文医学中心），是眼睛发育和信号途径的专家。 我的科学顾问Melinda Duncan博士和Peter Sims博士将获得其他建议。 晶状体发育和单细胞RNA - 后期。沿着职业发展的资源 哥伦比亚大学的研究环境非常适合我过渡到独立研究者 研究眼睛发育和疾病的信号传导机制。