The Role of Adenosine in Retinal Ischemia

腺苷在视网膜缺血中的作用

• 批准号: 7811729
• 负责人: STEVEN ROTH
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811729
• 关键词: Abbreviations; Adenosine; Analysis of Variance; Apoptosis; Applications Grants; Arts; Atherosclerosis; Biochemical; Biochemistry; Biotin; Blindness; Blood flow; Cell Death; Cells; Clinical; Complex; Data; Diabetes Mellitus; Disease; Electroretinography; Environment; Erythropoietin; Extracellular Signal Regulated Kinases; Funding; Ganglion Cell Layer; Gene Expression; Glaucoma; Grant; Injury; Inner Nuclear Layer; Inner Plexiform Layer; Interleukins; Ischemia; Ischemic Preconditioning; Knowledge; Label; Lead; Mediating; Methodology; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nuclear; Pathogenesis; Phosphorylation; Physiologic Intraocular Pressure; Potassium; Potassium Channel; Protein Kinase C; Proto-Oncogene Proteins c-akt; Protocols documentation; Purine Nucleosides; RNA; Rattus; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Research Design; Retina; Retinal; Retinal Ganglion Cells; Retinopathy of Prematurity; Role; Signal Transduction; Small Interfering RNA; Solutions; Stimulus; Time; Translations; Vascular Diseases; Venous; attenuation; base; citrate carrier; conditioning; cytochrome c oxidase; dihydroethidium; disability; human NOS3 protein; in vivo; innovation; insight; knock-down; mitochondrial permeability transition pore; mitogen-activated protein kinase p38; neuroprotection; new technology; outer plexiform layer; preconditioning; prevent; protective effect; public health relevance; receptor; response; retinal ischemia; salt balance; stress-activated protein kinase 1

DESCRIPTION (provided by applicant): This competitive revision application seeks additional funding for new aims that are being proposed for original grant application RO1EY10343. The original application sought funds to further our studies of the mechanisms of ischemic preconditioning (IPC) in the rat retina in vivo. IPC is a brief period of ischemia that is capable of inducing robust tolerance to the effects of damaging ischemia. Thus, IPC provides neuroprotection, and the study of its mechanisms is expected to lead to clinically translatable means to prevent ischemic injury. Significant visual loss may result from retinal ischemia in retinal arterial or venous occlusion, glaucoma, atherosclerosis, or in systemic disorders such as diabetes mellitus. Because treatment of these disorders remains unsatisfactory, the prospect of activating endogenous neuroprotective mechanisms is exciting and of significance to preventing these disorders that result in significant disability. We also recently observed that an even more robust neuroprotection could be induced by placing the brief ischemic stimulus AFTER the damaging ischemia, which is the reverse of the protocol used in preconditioning. This effect is known as post- conditioning. Preliminary data presented in this proposal support the protective effect of post-conditioning (Post-C), but also suggest that the mechanisms, while related, may not be the same as IPC. Examining mechanisms of Post-C has the potential to yield new insights into endogenous neuroprotection in the retina. Moreover, Post-C, unlike IPC, may itself be directly applied clinically, after an episode of ischemia. Accordingly, we propose a competitive revision that will expand our studies into a new specific aim, i.e., to examine the mechanisms of Post-C. We hypothesize that Post-C alters the molecular environment of retinal cells during reperfusion following ischemia, via activation of MAP kinases. The research design in this competitive revision builds upon that used in the currently funded grant, adding detailed study of the MAP kinases. We will use innovative methodology developed during the current period, i.e., the use of interfering RNA to procude a targeted, specific knock down in vivo of MAP kinase subtypes. Combining state of art retinal functional electrophysiological assessment, histological examination, and characterization of cell death and molecular mechanisms by both well established and newer technologies, we will use a powerful and robust model to elucidate the mechanisms of a promising means to induce endogenous neuroprotection in the retina. PUBLIC HEALTH RELEVANCE: Combining state of art retinal functional electrophysiological assessment, histological examination, and characterization of cell death and molecular mechanisms by both well established and newer technologies, we will use a powerful and robust model to elucidate the mechanisms of a promising means to induce endogenous neuroprotection in the retina.

描述（由申请人提供）：此竞争性修订申请寻求额外的资金，用于为原始赠款申请RO 1 EY 10343提出的新目标。最初的申请寻求资金，以进一步我们的研究缺血预处理（IPC）在大鼠视网膜在体内的机制。IPC是一个短暂的缺血期，能够诱导对损伤性缺血效应的强大耐受。因此，IPC提供了神经保护，并且对其机制的研究有望导致临床上可转化的预防缺血性损伤的方法。视网膜动脉或静脉阻塞、青光眼、动脉粥样硬化或糖尿病等全身性疾病中的视网膜缺血可能导致显著的视力丧失。由于这些疾病的治疗仍然不令人满意，激活内源性神经保护机制的前景是令人兴奋的，并且对于预防这些导致显著残疾的疾病具有重要意义。我们最近还观察到，在损伤性缺血后进行短暂的缺血刺激可以诱导更强的神经保护作用，这与预处理中使用的方案相反。这种效应被称为后适应.本提案中提供的初步数据支持后处理（Post-C）的保护作用，但也表明，这些机制虽然相关，但可能与IPC不同。检查后C的机制有可能产生新的见解视网膜内源性神经保护。此外，与IPC不同，Post-C本身可以在缺血发作后直接应用于临床。因此，我们提出了一个有竞争力的修订，将我们的研究扩展到一个新的具体目标，即，探讨Post-C的作用机制。我们推测，后C改变视网膜细胞的分子环境，在缺血再灌注后，通过激活MAP激酶。这项竞争性修订的研究设计建立在目前资助的赠款中使用的基础上，增加了对MAP激酶的详细研究。我们将采用本期间开发的创新方法，即，使用干扰RNA在体内产生MAP激酶亚型的靶向特异性敲低。结合最先进的视网膜功能电生理评估，组织学检查，以及细胞死亡和分子机制的表征，我们将使用一个强大而强大的模型来阐明一个有前途的手段，以诱导内源性神经保护视网膜的机制。 公共卫生相关性：结合最先进的视网膜功能电生理评估，组织学检查，以及细胞死亡和分子机制的表征，我们将使用一个强大而强大的模型来阐明一个有前途的手段，以诱导内源性神经保护视网膜的机制。