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; 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 潜在的视网膜突触和细胞生理学介导视觉图像处理，以及2）早期 细胞变化可能会介导视网膜和视神经后的神经节细胞死亡和视力丧失 神经疾病和创伤。该程序由两个相关组件组成。 1）国家卫生研究所支持的研究与职能组织有关 哺乳动物视网膜通过研究突触和细胞机制，以及视网膜微电路在 中介图像处理。这个基本的实验组件集中于两类的视网膜 中间神经元，称为悬氨酸和水平细胞，其网络连接以及其作用 在定义的视网膜电路中起作用的信号分子。这些研究旨在促进我们的知识 正常的细胞机制，介导视网膜中的视觉信息处理。此信息是关键 了解眼病的病理生理学，这是发展理性遗传和 干细胞治疗方法预防或治疗视网膜疾病，例如青光眼，黄斑 变性和糖尿病性视网膜病，影响退伍军人人口。 2）VA支持的研究涉及了解视网膜神经节背后的早期机制 因视网膜和视神经疾病和损伤而导致的细胞死亡。眼部创伤，经常发生 创伤性脑损伤（TBI），导致严重的视觉障碍，包括敏锐度丧失，恐惧症和 部分和完全视力丧失。当前的功绩审查集中于Ca2+通道和钙可渗透 AMPA受体（CP-AMPAR）转录和翻译调节以及神经节细胞内CA2+ 视神经损伤后，作为视神经创伤的模型。第一组研究的重点是L- 由神经节细胞表达的Ca2+通道类型，以阐明L型Ca2+通道阻滞剂的作用， Lomerizine，可在不同模型的视神经病模型中增强神经节细胞的存活。研究是 评估视神经损伤后L型Ca2+通道表达和功能，并测试以下想法 Lomerizine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 CA2+涌入。反过来，这将限制包括神经节细胞损失在内的病理变化。动物研究测试 还计划针对视网膜神经节细胞存活进行Lomerizine给药。相关的实验研究 专注于测试是否在视网膜神经节细胞上迅速上调的CP-Ampars是否 眼损伤后的树突，介导Ca2+摄取神经节细胞，并导致神经节细胞死亡。 实验的重点是定义CP-Ampar和AMPAR编辑酶表达，并进行测试 药理学对抗，遗传和siRNA介导的CP-Ampars和 AMPA编辑酶ADAR2稳定神经节细胞内Ca2+水平，并增强神经节细胞 神经损伤后的生存。动物研究还将测试选择性的CP-Ampar拮抗剂和针对性的 siRNA防止视神经损伤后的视网膜神经节细胞损失。 优异审查研究的长期目标是了解与视网膜相关的视力丧失 神经节细胞死亡可以减少。这些研究具有揭示新型治疗的潜在影响 改善眼部损害和视力丧失的方法。这些调查与 退伍军人事务部与健康相关的目标，以开发有效的眼睛损伤治疗方法。