Retinal Ganglion Cell Signaling Regulated By Intrinsic Reactive Oxygen Species

视网膜神经节细胞信号传导受内在活性氧的调节

• 批准号: 10588039
• 负责人: Steven Andrew Barnes
• 金额: $ 39.25万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588039
• 关键词: Action Potentials; Afferent Neurons; Axon; Bathing; Bioenergetics; Biophysical Process; Blindness; Brain; Cell physiology; Cells; Clinical; Code; Complex; Data; Detection; Diagnosis; Diagnostic; Environment; Excision; Expenditure; Failure; Feedback; Frequencies; Generations; Goals; Health; Inherited; Intervention; Investigation; Ion Channel; Ion Channel Gating; Ions; Kinetics; Knowledge; Light; Light Cell; Link; Mediating; Membrane; Metabolic; Metabolic stress; Metabolism; Mitochondria; Modeling; Mus; National Eye Institute; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Optic Nerve; Output; Oxidants; Patch-Clamp Techniques; Pathologic; Pattern; Phenotype; Play; Predisposition; Process; Production; Property; Proteins; Reactive Oxygen Species; Research; Resolution; Retina; Retinal Diseases; Retinal Ganglion Cells; Shapes; Signal Transduction; Stimulus; Stress; Synapses; Testing; Vision; Visual; biophysical properties; cost; ganglion cell; improved; insight; light intensity; neural; neuroprotection; novel; optic nerve disorder; patch clamp; prevent; protein expression; response; retinal neuron; sight restoration; stem; theories; tool; transmission process; visual information; visual stimulus; voltage; voltage clamp

Project Abstract This proposal to investigate the impact of the bioenergetically-regulated, metabolic environment on the sensitivity and signaling of retinal ganglion cells blends two converging lines of inquiry. The first arises from evidence that neuronal metabolic stress is accommodated within diverse and complex solutions. The second stems from our extensive knowledge of ganglion cell signaling functions, some of which we now interpret as adaptions to the consequences of fluctuating energy requirements. The focus of this proposal is on identified ganglion cell responses to light and how changes to specific response features are modulated by intrinsic metabolic activity. There is a gap in our understanding of how the different response-forming functions of cellular excitability may be changed during metabolic stress as well as the degree of the consequences of these changes to ganglion cell sensitivity and visual function overall, especially during the pathological conditions that lead to ganglion cell loss. Our investigations will test hypotheses that intersect at the bioenergetic state of the retina and its effects on the signaling of ganglion cells. In Specific Aim 1, we will define how the normal environmental conditions of the outer retina contribute to the response features of ganglion cells. We will test the hypothesis that intrinsic metabolic activity has a key influence on ganglion cell light responses by comparing controlled oxidant modulation of the cells' response waveforms. In Specific Aim 2, we will characterize the oxidant sensitivity of the cells' excitability mechanisms responsible for ganglion cell action potential generation. We will test the hypothesis that the metabolic activity of each ganglion cell and its neighbors influences these signaling mechanisms via oxidant production. In Specific Aim 3, we will examine the net influence of metabolic modulation caused by light intensity changes (contrast adaptation) on ganglion cell output. We will test how the actions of oxidants on specific features of the ganglion cell responses reflect the cell's metabolic state, and how they adjust retinal output in normal and pathophysiological conditions. These proposed studies will further our understanding of the cellular mechanisms that underlie ganglion cell responses and retinal output. Our objectives are consistent with the health-related goals of the National Eye Institute for understanding neuroprotective mechanisms in retinal neurons to prevent neurodegeneration, including that induced by excessive levels of metabolic byproducts, as well as understanding the origin of dysfunctional retinal signals that are detected with clinical tools essential for diagnosing and assessing the progression of retinal disease.

项目摘要 该提案旨在研究生物能量调节的代谢环境对 视网膜神经节细胞的敏感性和信号传导融合了两条交汇的探究线。第一个源于 有证据表明神经元代谢应激可以在多种复杂的解决方案中得到调节。第二个 源于我们对神经节细胞信号传导功能的广泛了解，其中一些我们现在解释为 适应能源需求波动的后果。该提案的重点是确定 神经节细胞对光的反应以及特定反应特征的变化如何受到内在的调节 代谢活动。我们对不同反应形成功能如何发挥作用的理解存在差距 细胞兴奋性可能会在代谢应激过程中发生变化，以及这些后果的程度 神经节细胞敏感性和视觉功能的整体变化，尤其是在病理条件下 导致神经节细胞损失。 我们的研究将测试与视网膜生物能状态相交的假设及其对视网膜的影响 神经节细胞的信号传导。在具体目标 1 中，我们将定义正常环境条件如何 外视网膜有助于神经节细胞的反应特征。我们将检验内在假设 通过比较受控氧化剂，代谢活动对神经节细胞光反应具有关键影响 细胞响应波形的调制。在具体目标 2 中，我们将表征氧化敏感性 细胞的兴奋机制负责神经节细胞动作电位的产生。我们将测试 假设每个神经节细胞及其邻近神经节细胞的代谢活动影响这些信号传导 通过氧化剂产生的机制。在具体目标 3 中，我们将检查代谢的净影响 光强度变化（对比度适应）对神经节细胞输出造成的调节。我们将测试如何 氧化剂对神经节细胞反应的特定特征的作用反映了细胞的代谢状态，并且 他们如何在正常和病理生理条件下调整视网膜输出。 这些拟议的研究将进一步我们对神经节细胞背后的细胞机制的理解 反应和视网膜输出。我们的目标与国家之眼的健康相关目标一致 了解视网膜神经元的神经保护机制以预防神经变性的研究所， 包括由代谢副产物水平过高引起的，以及了解 通过临床工具检测到的功能失调的视网膜信号对于诊断和评估至关重要 视网膜疾病的进展。