Dopamine Mediated Control of Retinal Vascular Integrity

多巴胺介导的视网膜血管完整性控制

• 批准号: 10705700
• 负责人: Melanie A Samuel
• 金额: $ 63.79万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705700
• 关键词: Amacrine Cells; Basic Science; Biology; Blood Vessels; Catecholamines; Cells; Coupling; Cues; DRD2 gene; DRD4 gene; Data; Development; Diabetic Retinopathy; Disease; Dopamine; Dopamine Receptor; Etiology; Experimental Designs; Eye diseases; Failure; Feedback; Foundations; Future; Genetic; Growth; Health; Homeostasis; Human; Hypoxia; Knowledge; Lead; Maintenance; Measures; Mediating; Molecular Target; Myopia; Nanotubes; Neuromodulator; Neurons; Oxygen; Pathology; Pathway interactions; Pattern; Pericytes; Physiology; Production; Public Health; Regulation; Retina; Retinal Ganglion Cells; Role; Signal Transduction; Source; Specific qualifier value; Testing; VEGFA gene; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vision; Visual System; Work; cell type; density; dopaminergic neuron; experimental study; gain of function; interest; loss of function; neurovascular unit; novel; novel therapeutics; prevent; response; retina blood vessel structure; retinal neuron; targeted treatment; vascular abnormality; vessel regression

PROJECT SUMMARY Dopamine is a neuromodulator with a critical role in vascular diseases of the eye. Our recent studies show that dopamine can directly signal to the vasculature via dopamine receptors and act as a developmental timing cue for hyaloid vascular regression through its regulation of VEGF. Here, we now extend these studies to the retina vasculature. Our preliminary data show that increasing dopamine signaling in the developing retina decreases vascular density, while decreasing dopamine causes vasculature overgrowth. We further identify retinal ganglion cells as novel dopamine producing cells and show that they directly modulate vascular growth. This is an important finding because dopamine was previously thought to be produced only by a subset of amacrine cells. To understand the mechanisms by which RGCs become dopaminergic and the vascular pathways through which they signal, we propose three experimental aims. We test whether dopamine has a direct (Aim 1) or indirect (Aim 2) effect on retinal vascular cells using vascular and neuron cell-specific strategies to remove dopamine receptors. We also ask whether dopamine and VEGFA function in trophic feedback within the retina to establish causation. In Aim 3, we determine the neuronal mechanisms by which RGC-derived dopamine modulates the vasculature through examination of the temporal and genetic pathways that regulate these unique cells. Identification of a dopaminergic-RGC dependent mechanism for modifying vasculature development and homeostasis is unexpected, so when completed this work will change the way we understand dopamine signaling and its distinct cellular roles. This work will also guide future efforts aimed at developing new therapeutic options to target retina vasculopathies.

项目摘要 多巴胺是一种神经调节剂，在眼睛的血管疾病中起关键作用。我们最近的研究表明 多巴胺可以通过多巴胺受体直接向脉管系统发出信号，并充当发展时间提示 通过调节VEGF的透明血管回归。在这里，我们现在将这些研究扩展到视网膜 脉管系统。我们的初步数据表明，发育中的视网膜中增加多巴胺信号传导降低 血管密度，同时减少多巴胺会导致脉管系统过度生长。我们进一步确定视网膜 神经节细胞作为新型多巴胺产生细胞，并表明它们直接调节血管生长。这是 一个重要的发现，因为以前认为多巴胺仅是由一部分的一部分产生的 细胞。了解RGC成为多巴胺能和血管途径的机制 通过它们发出信号，我们提出了三个实验目标。我们测试多巴胺是否有直接（目标 1）或间接（AIM 2）使用血管和神经元细胞特异性策略对视网膜血管细胞的影响 去除多巴胺受体。我们还询问多巴胺和VEGFA在营养反馈中是否功能 建立因果关系的视网膜。在AIM 3中，我们确定了RGC衍生的神经元机制 多巴胺通过检查调节的时间和遗传途径来调节脉管系统 这些独特的细胞。鉴定多巴胺能-RGC依赖性机制，用于修饰脉管系统 发展和体内平衡是出乎意料的，因此完成后，这项工作将改变我们的方式 了解多巴胺信号传导及其独特的细胞作用。这项工作还将指导针对未来的努力 开发新的治疗选择来靶向视网膜血管疾病。