FGFS--REGULATORS OF NEURAL DIFFERENTIATION IN THE RETINA

FGFS--视网膜神经分化的调节因子

基本信息

批准号：
2545828
负责人：
JOHN A WAGNER
金额：
$ 23.02万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-01 至 1999-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2545828
关键词：
amine oxidoreductase cytotoxicity developmental neurobiology fibroblast growth factor ischemia laboratory mouse nerve injury nervous system regeneration neuroprotectants neurotrophic factors nitric oxide oxidative stress photobiology retina retina circulation retinal pigment epithelium trauma

项目摘要

DESCRIPTION: (From Applicant's Abstract) The investigators are interested in the rational development of therapies that might either help repair or prevent damage to the visual system caused by disease or injury. Thus, it is important to understand both the ways the way the visual system responds to injury and the molecular mechanisms that damage the retina. The investigators propose studies of both FGF, a neuroprotective agent, and nitric oxide (NO), a potent neurotoxin, in ischemic damage, in photodamage, and in traumatic injury. They originally purified FGF from the retina as a molecule capable of stimulating neural differentiation. The FGFs can regulate the survival and differentiation of several cells in the PNS and CNS, including the retina. The investigators showed that there is are dramatic changes in the localization of FGF in response to injury to the optic nerve. In the first part of the application, the investigators will focus on the functional involvement of FGF and NO in two models of damage to the retina, photodamage and ischemic damage. The investigators' laboratory was the first to show that FGF can protect neurons is by making them resistant to NO, which is produced during excitotoxicity. The investigators have recently demonstrated that the RPE expresses a constitutively active form of Nitric Oxide Synthase in vivo. The investigators propose the hypothesis that NO may be a toxic agent that contributes to neural damage during ischemia or photodamage. FGF may confer resistance to NO toxicity by several mechanisms. In Aim 1, the investigators explore the hypothesis that FGF can protect photoreceptors against photodamage by conferring resistance to nitric oxide toxicity. The investigators will determine if NO is toxic to photoreceptors and they will determine if FGF protects by reducing the level of Nitric Oxide Synthase in vivo or by making photoreceptors more resistant to NO. In Aim 2, the investigators will develop and characterize a new model of retinal ischemia based on the four vessel occlusion model and use it (or the established IOP model of retinal ischemia) to determine whether ischemia induces the expression of either FGF of NOS in the retina. The investigators will also determine if generation of NO plays an important role in ischemic or excitotoxic death in the retina. In Aim 3, the investigators propose to determine which cells are responsible for the change in FGF expression after injury.This is a first step to determining how traumatic damage regulates the level of FGF in the retina. The investigators will also determine if damaging the optic nerve causes changes in the distribution of aFGF. By considering both the role of NO as a toxic agent and FGF as a protective agent, the investigators hope to be able to understand how the retina responds to damaging situations with the expectation that this knowledge may be a guide to therapeutic intervention. The information the investigators obtained will be of fundamental importance to pathologies that involve ischemia or excitotoxicity including occlusive vascular diseases, glaucoma, and vasoproliferative disorders.

描述：（从申请人的摘要中）调查人员有兴趣在理性的疗法中，可能有助于修复或防止疾病或伤害引起的视觉系统损害。因此，重要的是要了解视觉的方式系统应对伤害和损害分子机制视网膜。研究人员提出了两个FGF的研究神经保护剂和一氧化氮（NO），有效的神经毒素，中缺血性损害，在发生损伤和创伤性损伤中。他们最初从视网膜纯化的FGF作为分子能够刺激神经分化。 FGF可以调节生存以及PN和CN中几个细胞的分化，包括视网膜。调查人员表明，有巨大的变化 FGF响应视神经的损伤的定位。在申请的第一部分中，调查人员将专注于 FGF的功能参与，在两种损坏模型中的功能参与视网膜，光损伤和缺血性损害。研究人员的实验室是第一个证明FGF可以保护神经元的人是使它们成为对NO的抗性，这是在兴奋性毒性期间产生的。这调查人员最近表明RPE表示一氧化氮合酶在体内的组成活性形式。这调查人员提出以下假设：不可以在缺血或光损伤期间导致神经损伤。 fgf可能通过多种机制赋予对无毒性的抗性。在AIM 1中研究人员探讨了FGF可以保护光感受器的假设通过赋予对一氧化氮毒性的耐药性来对抗光损伤。调查人员将确定不对感光器和他们将通过降低一氧化氮的水平来确定FGF是否可以保护体内合成酶或通过使光感受器对NO的抗性更具耐药性。在AIM 2中，调查人员将开发并表征一个新的模型基于四个容器闭塞模型的视网膜缺血并使用它（或既定的视网膜缺血模型），以确定是否是否缺血在视网膜中诱导任何一个NOS的表达。这调查人员还将确定是否发挥不发挥作用是否重要视网膜中缺血性或兴奋性死亡的作用。在AIM 3中，研究人员建议确定哪些细胞是负责受伤后FGF表达的变化。这是确定创伤性损害如何调节FGF水平的第一步在视网膜中。调查人员还将确定是否损坏视神经会导致AFGF分布的变化。通过考虑NO作为有毒剂的作用和FGF的作用保护剂，调查人员希望能够了解视网膜应对破坏情况，并期望这些知识可能是治疗干预的指南。这研究人员获得的信息将非常重要涉及缺血或兴奋性毒性的病理闭塞性血管疾病，青光眼和血管增生性疾病。