Mechanisms of neurovascular coupling in the retina and their dysfunction in diabetes

视网膜神经血管耦合机制及其在糖尿病中的功能障碍

• 批准号: 10612782
• 负责人: Zachary Jessen
• 金额: $ 5.27万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612782
• 关键词: Adult; Affect; Amacrine Cells; Angiography; Area; Biological Models; Blindness; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Calcium; Cardiovascular system; Cell Communication; Cells; Central Nervous System; Clinical; Complications of Diabetes Mellitus; Computer Models; Darkness; Diabetes Mellitus; Diabetic Microangiopathies; Diabetic Retinopathy; Diabetic mouse; Diameter; Diffusion; Disease; Electrical Synapse; Electrophysiology (science); Eye; Functional disorder; Future; Ganglion Cell Layer; Glucose; Health; Human; Hyperglycemia; Image; Individual; Inner Nuclear Layer; Inner Plexiform Layer; Intervention; Light; Measurement; Measures; Metabolic; Microscope; Modeling; Modernization; Monitor; Mus; Nerve Degeneration; Nervous System; Neuroglia; Neurons; Neurosciences; Nitric Oxide; Nitric Oxide Pathway; Nutrient; Optical Coherence Tomography; Oxygen; Pathology; Patients; Pattern; Pericytes; Persons; Pharmacology; Photoreceptors; Play; Preparation; Public Health; Regulation; Research; Research Project Grants; Retina; Role; Signal Transduction; Stimulus; Structure; System; Techniques; Time; Transgenic Mice; Vascular Diseases; Visual impairment; Visualization; Work; arteriole; biopsychosocial; constriction; impaired capacity; insight; mathematical model; neural; neurotransmission; neurovascular coupling; outer plexiform layer; patch clamp; reconstruction; response; retina circulation; retinal neuron; sugar; targeted treatment; tissue fixing; translational goal; two-photon; vascular abnormality; visual stimulus

Project Summary One of the defining features of blood circulation in the central nervous system is its capacity to be regulated by signaling from neurons and glia. In the retina, this feature, termed neurovascular coupling (NVC), occurs on the level of larger arterioles down to individual capillaries. Dilation and constriction of these capillaries is controlled by vasoactive cells called pericytes. The retinal vasculature is organized in an expansive network of three laminae which supply nutrients to distinct types of neurons organized in corresponding layers. Previous work has shown that flow through each lamina is differentially regulated by light, but the mechanisms of NVC in the retina and how they could differ between laminae remain poorly understood. Revealing the mechanisms of NVC in the retina is an important public health concern because there is a growing body of evidence that NVC dysfunction is critical to the pathology of diabetic retinopathy, a blinding disease affecting 35% of patients with diabetes. Treatments for diabetic retinopathy are targeted towards late- stage vascular complications, but there are no current treatments targeted towards NVC dysfunction. This project seeks to determine the underlying parameters of light stimulus that lead to vasoactivity in the retina and the cellular mechanisms that make this possible. I will use electrophysiology and two-photon imaging to measure pericyte activity and capillary diameter in the ex vivo mouse retina, and I will develop a computational model of blood flow and nutrient diffusion throughout the retina. I will also explore the role of hyperglycemia in the NVC dysfunction seen in diabetes. Successful completion of this project will lead to a better understanding of how blood flow in the central nervous system is regulated, potential targets for therapy, and the establishment of a model system for future explorations of how the nervous and circulatory systems are intertwined.

项目摘要 中枢神经系统中血液循环的定义特征之一是其受到调节的能力 来自神经元和神经胶质的信号传导。在视网膜中，此特征称为神经血管耦合（NVC），发生在 较大的小动脉的水平降至单个毛细血管。这些毛细血管的扩张和收缩受到控制 通过称为周细胞的血管活性细胞。视网膜脉管系统是在三个宽阔的网络中组织的 薄片为在相应层中组织的不同类型的神经元提供营养。以前的工作 已经表明，通过光线通过光差异调节，但是NVC的机理 视网膜及其在薄片之间如何有所不同仍然知之甚少。 揭示视网膜中NVC的机制是一个重要的公共卫生问题，因为有一个 越来越多的证据表明NVC功能障碍对糖尿病性视网膜病的病理至关重要，这是一种盲目的 影响35％的糖尿病患者的疾病。糖尿病性视网膜病治疗的目标是晚期 阶段血管并发症，但目前没有针对NVC功能障碍的治疗方法。 该项目旨在确定导致在 视网膜和导致这一可能的细胞机制。我将使用电生理学和两光子 成像以测量离体小鼠视网膜中的周细胞活性和毛细血管直径，我将发展一个 整个视网膜的血流和营养扩散的计算模型。我还将探索 NVC功能障碍中的高血糖症在糖尿病中可见。成功完成该项目将导致 更好地了解中枢神经系统中的血液流量如何受到调节，潜在的治疗靶标， 以及建立模型系统，以探索未来的神经和循环系统 交织在一起。