Control of retinal angiogenesis by Tbx3

Tbx3 对视网膜血管生成的控制

• 批准号: 10510908
• 负责人: ANDREA S VICZIAN
• 金额: $ 24.45万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510908
• 关键词: Address; Adult; Affect; Astrocytes; Automobile Driving; Bacterial Artificial Chromosomes; Blindness; Blood Vessels; Cells; Cre driver; Data; Defect; Development; Diffuse; Dorsal; Embryo; Endothelial Cells; Eye; Foundations; Future; Genes; Genetic; Genetic Transcription; Goals; Grant; Growth; Lead; Maintenance; Mediator of activation protein; Molecular; Mus; Pathway interactions; Penetrance; Photosensitivity; Play; Population; Process; Rana; Reporting; Retina; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Signaling Protein; Tamoxifen; Testing; Tissues; Validation; WNT Signaling Pathway; Work; angiogenesis; blood vessel development; cadherin 5; cell type; conditional knockout; congenic; experimental study; eye formation; novel; optic cup; postnatal; retina blood vessel structure; retinal angiogenesis; retinal progenitor cell; single-cell RNA sequencing; transcription factor

Project Summary/Abstract Retinal vascular disruption, either during development or in adulthood, remains a major cause of blindness, yet the underlying molecular mechanisms guiding their formation and survival remain largely unknown. Retinal ganglion cells (RGCs), being the first to differentiate, express diffusible molecules that trigger the entry of astrocytes and endothelial cells into the retina, leading to formation of the vasculature. Thus, understanding the transcription factor network expressed in RGCs and endothelial cells is critical for formation and maintenance of retinal vasculature. Our group has shown that the transcription factor, TBX3, plays a critical role in this process. We previously found that TBX3 is required for eye formation in frog, yet its role in mammalian eye formation remained unknown. A confounding issue was that the first reported genetic disruption of Tbx3 was actually a hypomorph with incomplete penetrance. Thus, to address the role of TBX3 in eye formation, we have turned to analyze a validated conditional knockout of Tbx3 from retinal tissues. Using this mouse, we have compelling preliminary data showing Tbx3 is required for intrinsically photosensitive retinal ganglion cell (ipRGC) formation and is also expressed by, and essential for, normal retinal endothelial cell formation. In Aim 1, we will determine which RGCs require TBX3 and we will perform an unbiased search for TBX3 transcriptional targets. In Aim 2, we characterize how the loss of Tbx3 affects Wnt signaling in endothelial cells and if TBX3 is required by endothelial cells for retinal vasculature formation. At the completion of this exploratory R21, we will have laid the foundation to determine the cell types and transcriptional targets most affected by Tbx3 loss, so that future experiments can further examine key factors essential for RGC and vascular formation in the retina.

项目摘要/摘要 视网膜血管破裂，无论是在发育过程中还是在成年期，仍然是导致 失明，然而指导它们形成和生存的潜在分子机制仍然存在 很大程度上是未知的。视网膜神经节细胞(RGC)是最先分化的细胞，表达弥漫性 触发星形胶质细胞和内皮细胞进入视网膜的分子，导致 血管系统的形成。因此，理解转录因子网络表达在 视网膜神经节细胞和内皮细胞对视网膜血管的形成和维持至关重要。我们的 研究小组已经证明，转录因子TBX3在这一过程中起着关键作用。我们 先前发现，TBX3是青蛙眼睛形成所必需的，但它在哺乳动物眼睛中的作用 编队仍不清楚。一个令人困惑的问题是，第一个报告的基因破坏 Tbx3实际上是一种不完全外显的低形体。因此，要解决以下问题： 在眼睛形成中，我们已经转向分析从 视网膜组织。使用这个鼠标，我们有令人信服的初步数据表明需要TBX3 对于固有的光敏性视网膜神经节细胞(IpRGC)的形成， 对于正常的视网膜内皮细胞的形成也是必不可少的。在目标1中，我们将确定哪一个 RGC需要TBX3，我们将对TBX3转录靶点进行无偏见的搜索。在……里面 目的2，我们研究了Tbx3的缺失如何影响内皮细胞中的Wnt信号，以及如果 Tbx3是内皮细胞形成视网膜血管所必需的。在完成这项工作后 探索性的R21，我们将为确定细胞类型和转录奠定基础 受TBX3损失影响最大的目标，以便未来的实验可以进一步检查关键因素 对视网膜的RGC和血管形成是必不可少的。