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: 10449631
• 负责人: Qian Wang
• 金额: $ 11.82万
• 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/10449631
• 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; Epithelial Cells; 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; Pathogenesis; Pattern; Phase; Phenotype; Preventive; Preventive Medicine; Raptors; Regulation; Regulatory Pathway; Research; Research Personnel; Resources; Risk; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Transcriptional Regulation; Universities; Vesicle; Visual impairment; WNT Signaling Pathway; base; 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.

项目总结/摘要 眼前节发育不全（ASD）是指影响眼睛前部的一系列疾病，包括 角膜、虹膜/睫状体和透镜。在特征性ASD基因中，大多数编码转录 因素然而，控制这些转录因子的上游信号事件尚不清楚。我的长- 长期目标是建立基因调控网络，支持眼前节的发展， 眼睛，以确定用于疾病预防和治疗的分子靶点。本提案的目的 是研究透镜发育中的信号网络和转录程序。特别是，我发现 雷帕霉素复合物1（mTORC 1）信号传导作为透镜囊泡形成中的新型调节剂的机制靶标。 我建议研究mTORC 1的上游调节因子和下游靶点，使用 条件性敲除小鼠和原代透镜上皮细胞模型的组合。我的中心假设是 成纤维细胞生长因子（FGF）信号激活透镜上皮细胞中的mTORC 1（Aim 1）， 在透镜囊泡形成过程中，mTORC 1信号通过调节Wnt信号来控制细胞粘附（Aim 2）。在目标1中，我将阐明FGF信号如何激活透镜中的mTORC 1的潜在机制 上皮在目标2中，我将研究mTORC 1如何调节Wnt信号传导以及Wnt信号传导的功能意义。 mTORC 1-Wnt轴在透镜上皮细胞粘附连接形成中的作用。此外，我建议确定 通过单细胞RNA测序在透镜囊泡形成期间mTORC 1介导的转录程序。这 该建议是创新的，因为它确定了透镜囊泡发育中的新的调节途径。它还链接 信号通路和转录因子，以阐明透镜囊泡发育的机制， 发病机理这项研究的结果是重要的，因为它们预计将影响 了解透镜囊泡的正常和有缺陷的发展，并有可能揭示新的 用于预防由先天性透镜缺陷引起的疾病的分子靶点。 本项目的辅导阶段将在张欣博士和卡罗尔·梅森博士的指导下进行 （哥伦比亚大学欧文医学中心），他们是眼睛发育和信号通路方面的专家。 我将从我的科学顾问梅林达邓肯博士和彼得西姆斯博士那里获得关于方面的其他建议 透镜发育和单细胞RNA测序。职业发展资源沿着 我在哥伦比亚大学的研究环境非常适合我成为一名独立调查员 研究眼睛发育和疾病的信号机制。