BLR&D Research Career Scientist Award

BLR

• 批准号: 10451508
• 负责人: NICHOLAS C. BRECHA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451508
• 关键词: AMPA Receptors; Acetylcholine; Address; Affect; Aging; Amacrine Cells; Animals; Award; Axon; Biology; Blindness; Blurred vision; Calcium; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Communication; Communities; Cytoprotection; DRADA2b protein; Dendrites; Development; Diabetic Retinopathy; Diagnosis; Disease; Enzymes; Eye; Eye Injuries; Eye diseases; Feedback; Functional disorder; Funding; Genetic; Glaucoma; Goals; Health; Healthcare; Injury; Interneurons; Investigation; Knowledge; Long-Term Effects; Macular degeneration; Mammals; Mediating; Modeling; Nature; Neurons; Optic Nerve; Optic Nerve Injuries; Paper; Pathologic; Peer Review; Peptides; Permeability; Pharmacology; Pharmacology Study; Photophobia; Play; Population; Prosthesis; Publishing; Quality of life; Recovery; Regulation; Reporting; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Role; Science; Scientist; Series; Signal Transduction; Signaling Molecule; Small Interfering RNA; Spermine; Stem cell transplant; Synapses; System; Testing; Transcriptional Regulation; Translational Regulation; Trauma; Traumatic Brain Injury; United States Department of Veterans Affairs; United States National Institutes of Health; Veterans; Vision; Vision research; Visual; Visual impairment; Visual system structure; aging population; antagonist; base; biophysical properties; blast exposure; career; cell type; channel blockers; disability; effective therapy; efficacious treatment; experimental study; extracellular; gabapentin; gamma-Aminobutyric Acid; ganglion cell; gene therapy; horizontal cell; image processing; information processing; mild traumatic brain injury; military veteran; nerve injury; novel therapeutic intervention; optic nerve disorder; patient population; prevent; programs; response; service member; stem cell therapy; treatment strategy; uptake; visual dysfunction; visual information

The long-term goal of this vision research program is to gain a better understanding of 1) the mechanisms underlying retinal synaptic and cellular physiology mediating visual image processing, and 2) the early cellular changes that are likely to mediate ganglion cell death and loss of vision following retinal and optic nerve disease and trauma. This program consists of two related components. 1) National Institute of Health supported studies are concerned with the functional organization of the mammalian retina by investigating synaptic and cellular mechanisms, and the role of retinal microcircuits in mediating image processing. This fundamental experimental component is focused on two classes of retinal interneurons, called amacrine and horizontal cells, their network connectivity, and the action of their signaling molecules that play a role in defined retinal circuits. These studies aim to advance our knowledge of normal cellular mechanisms mediating visual information processing in the retina. This information is key to understanding the pathophysiology of eye diseases, a required step for developing rational genetic and stem cell therapeutic approaches for preventing or treating retinal diseases such as glaucoma, macular degeneration, and diabetic retinopathy, which affect the Veteran population. 2) VA supported studies are concerned with understanding early mechanisms underlying retinal ganglion cell death due to retina and optic nerve disease and injury. Ocular trauma, which frequently occurs with traumatic brain injury (TBI), results in severe visual impairments, including acuity loss, photophobia, and partial and total loss of vision. The current Merit Review is focused on Ca2+ channel and calcium permeable AMPA receptor (CP-AMPAR) transcriptional and translational regulation and ganglion cell intracellular Ca2+ following optic nerve injury, as a model for optic nerve trauma. The first group of studies is focused on L- type Ca2+ channels expressed by ganglion cells, to elucidate the actions of the L-type Ca2+ channel blocker, lomerizine, which enhances ganglion cell survival in different models of optic neuropathy. Studies are evaluating L-type Ca2+ channel expression and function following optic nerve injury, and to test the idea that lomerizine blocks up-regulated Ca2+ channel function, which in turn slows intracellular retinal ganglion cell Ca2+ influx. This in turn would limit pathological changes including ganglion cell loss. Animal studies testing lomerizine administration on retinal ganglion cell survival are also planned. Related experimental studies are focused on testing if CP-AMPARs, which are reported to be rapidly up-regulated on retinal ganglion cell dendrites after ocular injury, mediate Ca2+ uptake into ganglion cells and contribute to ganglion cell death. Experiments are focused on defining CP-AMPAR and the AMPAR editing enzyme expression, and testing the idea that pharmacological antagonism, genetic and siRNA-mediated regulation of CP-AMPARs and the AMPA editing enzyme ADAR2 stabilize ganglion cell intracellular Ca2+ levels, and enhances ganglion cell survival following nerve injury. Animal studies will also test if selective CP-AMPAR antagonists and targeted siRNAs protect against retinal ganglion cell loss after optic nerve injury. The long-term goal of the Merit Review studies is to understand how vision loss associated with retinal ganglion cell death can be reduced. These studies have the potential impact of unveiling novel therapeutic approaches to ameliorate ocular damage and vision loss. These investigations are consistent with the health-related goals of the Department of Veteran Affairs to develop effective treatments for eye injuries.

该愿景研究计划的长期目标是更好地了解 1) 机制 介导视觉图像处理的潜在视网膜突触和细胞生理学，以及 2) 早期 可能介导神经节细胞死亡和视网膜和视神经损伤后视力丧失的细胞变化 神经疾病和创伤。该程序由两个相关的组件组成。 1) 美国国立卫生研究院支持的研究涉及医疗机构的职能组织 通过研究突触和细胞机制以及视网膜微电路在哺乳动物视网膜中的作用 中介图像处理。这个基本的实验部分重点关注两类视网膜 中间神经元，称为无长突细胞和水平细胞，它们的网络连接性以及它们的作用 在确定的视网膜回路中发挥作用的信号分子。这些研究旨在增进我们的知识 介导视网膜视觉信息处理的正常细胞机制。这些信息是关键 了解眼部疾病的病理生理学，这是发展合理的遗传和疾病的必要步骤 用于预防或治疗青光眼、黄斑等视网膜疾病的干细胞治疗方法 退化和糖尿病性视网膜病变，这些都会影响退伍军人群体。 2) VA 支持的研究涉及了解视网膜神经节的早期机制 由于视网膜和视神经疾病和损伤导致的细胞死亡。眼外伤，常发生于 创伤性脑损伤（TBI）会导致严重的视力障碍，包括敏锐度丧失、畏光和 部分和全部视力丧失。当前的优点评审重点是 Ca2+ 通道和钙渗透性 AMPA 受体 (CP-AMPAR) 转录和翻译调节与神经节细胞胞内 Ca2+ 视神经损伤后，作为视神经损伤的模型。第一组研究集中于 L- 神经节细胞表达的 Ca2+ 型通道，以阐明 L 型 Ca2+ 通道阻滞剂的作用， 洛美利嗪，可增强不同视神经病变模型中神经节细胞的存活率。研究是 评估视神经损伤后 L 型 Ca2+ 通道的表达和功能，并检验以下观点： 洛美利嗪阻断上调的 Ca2+ 通道功能，从而减慢细胞内视网膜神经节细胞的速度 Ca2+ 流入。这反过来又会限制包括神经节细胞损失在内的病理变化。动物研究测试 洛美利嗪对视网膜神经节细胞存活的影响也在计划中。相关实验研究 专注于测试 CP-AMPAR 是否在视网膜神经节细胞上快速上调 眼损伤后树突介导神经节细胞对 Ca2+ 的摄取并导致神经节细胞死亡。 实验重点是定义 CP-AMPAR 和 AMPAR 编辑酶表达，并进行测试 CP-AMPAR 的药理学拮抗作用、遗传和 siRNA 介导的调节以及 AMPA编辑酶ADAR2稳定神经节细胞胞内Ca2+水平，增强神经节细胞功能 神经损伤后的存活率。动物研究还将测试选择性 CP-AMPAR 拮抗剂和靶向药物是否 siRNA 可防止视神经损伤后视网膜神经节细胞损失。 优点审查研究的长期目标是了解视力丧失与视网膜有何关系 可以减少神经节细胞的死亡。这些研究具有揭示新疗法的潜在影响 改善眼部损伤和视力丧失的方法。这些调查符合 退伍军人事务部的健康相关目标是开发眼外伤的有效治疗方法。