Dysfunction of retinal neurons and circuits early in diabetic retinopathy

糖尿病视网膜病变早期视网膜神经元和回路功能障碍

• 批准号: 8697397
• 负责人: Rene Carlos Renteria
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697397
• 关键词: Affect; Age; Agonist; Behavior; Blindness; Blood Vessels; Blood capillaries; Blood flow; Brain; Capillary Endothelial Cell; Cell Survival; Chronic; Clinical Treatment; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Dopamine; Dopamine D2 Receptor; Endothelial Cells; FDA approved; Functional disorder; Gap Junctions; Human; Impairment; Knowledge; Lead; Link; Mediating; Mission; Mus; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathway interactions; Performance; Permeability; Physiology; Population; Process; Production; Public Health; Publishing; Receptor Activation; Research; Retina; Retinal; Role; Signal Transduction; Source; Synapses; System; Testing; Treatment outcome; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Varicosity; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilator Agents; Vision; Visual; Visual impairment; Work; arteriole; base; capillary; diabetic; dopaminergic neuron; functional disability; improved; innovation; insight; light intensity; neuromechanism; neuron loss; novel; paracrine; public health relevance; receptive field; receptor; retinal neuron

DESCRIPTION (provided by applicant): Dopaminergic amacrine neurons are the only source of dopamine in the retina. Released locally at synapse- like varicosities to target neurons and also in a paracrine fashion to diffusely affect the retina, dopamine is critical in adjusting the retina from nighttime to daytime vision. Intriguing data from published studies indicate that dopaminergic processes and varicosities closely associate with the retinal capillaries, not just neurons, but whether dopamine is vasoactive in retina as in brain is unknown. In this application, we will test the novel hypothesis that dopamine regulates both neuronal and vascular function of the retina and that dysregulation of dopamine action at neurons and capillary endothelial cells in diabetes contributes significantly to the visual impairments of diabetic retinopathy. We propose that dopamine production is reduced in diabetic retina, exacerbating the neuronal and vascular dysfunctions that we have determined to occur in the Ins2Akita mouse model of diabetes. This is based on our preliminary data that dopamine release, tyrosine hydroxylase expression, and dopaminergic neuron number are all reduced in diabetic Akita retina. Further, we find deficits in retinal circuit function, visual behavior, and lood flow that are all remarkably consistent with reduced dopamine as a unifying mechanism. This is of fundamental importance for advancing our basic understanding of retinal function and, importantly, represents a translationally significant new hypothesis that could lead to new targets for improved clinical treatment of diabetic retinopathy. This postulated reduction in dopamine would interfere with retinal function because the normal uncoupling of gap junction networks by dopamine is necessary for matching retinal sensitivity to mean light intensity and for modulating receptive field function. We have demonstrated a marked impairment in diabetic Akita mice of optokinetic tracking (OKT) (Akimov and Renteria, 2012), a visual behavior that requires dopamine for optimal performance. The mechanisms of these neural deficits and how they recapitulate visual dysfunctions in human diabetic retinopathy will be explored in detail in Aim 1. This is translationally significant because our studies will show that treatments that maintain dopamine signaling will ameliorate visual behavior deficits and that dopaminergic dysfunction occurs early in the pathogenesis of diabetic retinopathy. We further hypothesize that dopamine action on retinal endothelial cells is a second critical pathogenic pathway of reduced dopamine in diabetic retinopathy. We propose that reduced dopamine exacerbates VEGF-associated permeability and contributes to the poor ocular blood flow we find in Akita mice. Aim 2 pursues these new ideas of dopamine action on endothelial cells in the retina and their outcomes for retinal neurons. This application is innovative because this pathway could be exploited using FDA-approved treatments as a novel adjunct to anti-VEGF therapy to further block the vascular permeabilizing activity of VEGF. The overall impact of the proposed work is that it provides novel insight for understanding how vision loss occurs in diabetic retinopathy and provides a new pathway to target for therapy.

描述（由申请人提供）：多巴胺能无长突神经元是视网膜中多巴胺的唯一来源。多巴胺在突触样静脉曲张处局部释放到靶向神经元，并且还以旁分泌方式弥漫性地影响视网膜，多巴胺在将视网膜从夜间视觉调节到白天视觉中是关键的。来自已发表研究的有趣数据表明，多巴胺能过程和静脉曲张与视网膜毛细血管密切相关，而不仅仅是神经元，但多巴胺在视网膜中是否与大脑中一样具有血管活性尚不清楚。在这个应用程序中，我们将测试新的假设，多巴胺调节神经元和血管功能的视网膜和多巴胺的神经元和毛细血管内皮细胞在糖尿病中的作用失调，有助于显着的糖尿病视网膜病变的视觉障碍。我们认为糖尿病视网膜中多巴胺的产生减少，加剧了我们已经确定在Ins2秋田糖尿病小鼠模型中发生的神经元和血管功能障碍。这是基于我们的初步数据，多巴胺释放，酪氨酸羟化酶的表达，多巴胺能神经元的数量都减少糖尿病秋田视网膜。此外，我们发现视网膜回路功能，视觉行为和视网膜血流的缺陷都与多巴胺减少作为一种统一机制非常一致。这对于推进我们对视网膜功能的基本理解具有根本重要性，并且重要的是，代表了一个具有重要意义的新假设，该假设可能导致改善糖尿病视网膜病变临床治疗的新靶点。这种假定的多巴胺减少会干扰视网膜功能，因为多巴胺对间隙连接网络的正常解偶联对于使视网膜敏感性与平均光强度相匹配以及调节感受野功能是必要的。我们已经证明糖尿病秋田小鼠的视动追踪（OKT）明显受损（Akimov和Renteria，2012），这是一种需要多巴胺才能获得最佳表现的视觉行为。这些神经缺陷的机制以及它们如何重现人类糖尿病视网膜病变中的视觉功能障碍将在目标1中详细探讨。这是非常重要的，因为我们的研究将表明，维持多巴胺信号传导的治疗将改善视觉行为缺陷，并且多巴胺能功能障碍发生在糖尿病视网膜病变的发病早期。我们进一步假设，多巴胺对视网膜内皮细胞的作用是糖尿病视网膜病变中多巴胺减少的第二个关键致病途径。我们认为，多巴胺减少加剧了VEGF相关的渗透性，并有助于我们在秋田小鼠中发现的眼血流量差。目的2追求这些新的想法多巴胺作用于视网膜内皮细胞和视网膜神经元的结果。这种应用是创新的，因为这种途径可以使用FDA批准的治疗作为抗VEGF治疗的新辅助手段来进一步阻断VEGF的血管透化活性。拟议工作的总体影响是，它为了解糖尿病视网膜病变中视力丧失如何发生提供了新的见解，并为治疗提供了新的靶向途径。