BLR&D Research Career Scientist Award

BLR

• 批准号: 10618251
• 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/10618251
• 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 Study; Photophobia; 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 System; Visual impairment; aging population; antagonist; 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; neuroprotection; novel therapeutic intervention; optic nerve disorder; patient population; pharmacologic; 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.

这一视觉研究计划的长期目标是更好地了解1)机制 调节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 视网膜和视神经损伤后可能导致神经节细胞死亡和视力丧失的细胞变化 神经疾病和创伤。该计划由两个相关部分组成。 1)国家卫生研究所支持的研究关注的是 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 调停图像处理。这一基本的实验成分主要集中在两类视网膜上 中间神经元，称为无长突细胞和水平细胞，它们的网络连接，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。这些研究的目的是增进我们的知识 在视网膜中调节视觉信息处理的正常细胞机制。这一信息是关键 为了了解眼部疾病的病理生理学，开发合理的遗传和 预防或治疗青光眼、黄斑等视网膜疾病的干细胞治疗方法 变性和糖尿病视网膜病变，这影响了退伍军人群体。 2)VA支持的研究关注于了解视网膜神经节的早期机制 视网膜和视神经疾病和损伤导致的细胞死亡。眼外伤，这经常发生在 创伤性脑损伤(TBI)，导致严重的视觉损伤，包括视力丧失、畏光和 部分或全部失明。钙离子通道与钙通透性的研究进展 AMPA受体(CP-AMPAR)转录和翻译调节与神经节细胞内钙离子 视神经损伤后，作为视神经损伤的模型。第一组研究集中在L身上-- 神经节细胞表达的钙通道，为阐明L钙通道阻滞剂的作用， 洛美利嗪可提高不同视神经病变模型中神经节细胞的存活率。研究是 评价视神经损伤后L钙通道的表达和功能，并验证 洛美利嗪阻断上调的钙通道功能，进而减缓细胞内视网膜神经节细胞 钙离子内流。这反过来将限制包括神经节细胞丢失在内的病理变化。动物实验测试 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 他们的重点是测试CP-AMPAR，据报道，这种受体在视网膜神经节细胞上迅速上调 眼外伤后的树突，介导了神经节细胞对钙的摄取，导致了神经节细胞的死亡。 实验的重点是确定CP-AMPAR和AMPAR编辑酶的表达，并进行检测 认为CP-AMPAR的药理拮抗、遗传和siRNA介导的调节以及 AMPA编辑酶ADAR2稳定神经节细胞内钙离子水平，增强神经节细胞 神经损伤后的存活。动物研究也将测试选择性CP-AMPAR拮抗剂和靶向 SiRNA对视神经损伤后视网膜神经节细胞丢失具有保护作用。 Merit Review研究的长期目标是了解视力丧失与视网膜 神经节细胞死亡可以减少。这些研究具有揭开新疗法面纱的潜在影响 改善眼睛损伤和视力丧失的方法。这些调查与 退伍军人事务部与健康有关的目标是开发有效的眼伤治疗方法。