Dopamine Mediated Control of Retinal Vascular Integrity

项目摘要 多巴胺是一种神经调质，在眼部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血管系统发出信号， 玻璃体血管通过VEGF的调节而消退。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，在发育中的视网膜中增加多巴胺信号会减少 减少多巴胺会导致血管过度生长。我们进一步确定视网膜 神经节细胞作为新的多巴胺产生细胞，并显示它们直接调节血管生长。这是 这是一个重要的发现，因为多巴胺以前被认为只由无长突的一个子集产生。 细胞了解RGC成为多巴胺能神经元的机制和血管通路 我们提出了三个实验目标。我们测试多巴胺是否具有直接的（Aim 1)或间接（目的2）的作用，视网膜血管细胞使用血管和神经元细胞特异性的策略， 移除多巴胺受体我们还想知道多巴胺和VEGFA是否在细胞内的营养反馈中起作用。 视网膜来建立因果关系在目标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血管的时间和遗传途径来调节血管， 这些独特的细胞。多巴胺能-RGC依赖性血管修饰机制的鉴定 发展和稳态是出乎意料的，所以当完成这项工作将改变我们的方式， 了解多巴胺信号及其独特的细胞作用。这项工作还将指导今后的努力， 开发针对视网膜血管病变的新的治疗选择。

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.