Dopamine Mediated Control of Retinal Vascular Integrity

项目总结 多巴胺是一种神经调节剂，在眼部血管疾病中起着关键作用。我们最近的研究表明 多巴胺可以通过多巴胺受体直接向血管系统发出信号，并作为发育计时信号。 通过对血管内皮生长因子的调节，治疗玻璃体血管退行性变。在这里，我们现在将这些研究扩展到视网膜 脉管系统。我们的初步数据显示，在发育中的视网膜中增加多巴胺信号会减少 血管密度，而减少多巴胺会导致血管过度生长。我们进一步确定了视网膜 神经节细胞作为新的多巴胺产生细胞，并表明它们直接调节血管生长。这是 这是一项重要的发现，因为以前人们认为多巴胺只由一种非长春碱产生 细胞。了解视网膜节细胞成为多巴胺能细胞的机制和血管通路 通过它们发出的信号，我们提出了三个实验目标。我们测试多巴胺是否有直接的(目的) 1)或间接(目标2)使用血管和神经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是否在营养反馈中起作用 视网膜来确定因果关系。在目标3中，我们确定了RGC派生的神经元机制 多巴胺通过检查调节的时间和遗传途径来调节血管系统 这些独特的细胞。多巴胺能-RGC依赖的血管调节机制的鉴定 发展和动态平衡是意想不到的，所以当这项工作完成时，将改变我们 了解多巴胺信号及其不同的细胞作用。这项工作还将指导今后旨在 开发针对视网膜血管疾病的新治疗方案。

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.