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）：此竞争性修订申请为原始赠款申请RO1EY10343提供的新目标寻求额外的资金。最初的应用程序寻求资金，以进一步研究体内大鼠视网膜中缺血性预处理（IPC）的机制。 IPC是短暂的缺血时期，能够诱导对破坏性缺血影响的强大耐受性。因此，IPC提供了神经保护作用，其机制的研究有望导致可预防缺血性损伤的临床翻译手段。视网膜缺血，视网膜动脉或静脉阻塞，青光眼，动脉粥样硬化或全身性疾病（如糖尿病），可能导致重大视觉丧失。由于这些疾病的治疗仍然不令人满意，因此激活内源性神经保护机制的前景令人兴奋，并且对于防止这些疾病导致严重的残疾而言具有重要意义。我们最近还观察到，可以通过在损害缺血后放置简短的缺血刺激来引起更强大的神经保护作用，这是预处理中使用的方案的逆转。这种效果称为后期。本提案中介绍的初步数据支持了调节后（C）的保护作用，但也表明该机制虽然相关，但可能与IPC不同。检查后C的机制有可能在视网膜中对内源性神经保护产生新的见解。此外，与IPC不同，C-C之后本身可能在缺血性发作后直接在临床上使用。因此，我们提出了一项竞争性修订，将我们的研究扩展到新的特定目标，即检查后C的机制。我们假设C通过激活MAP激酶，在缺血后再灌注期间在再灌注过程中改变了视网膜细胞的分子环境。此竞争性修订中的研究设计基于当前资助的赠款中使用的研究设计，并增加了对地图激酶的详细研究。我们将使用在当前时期开发的创新方法，即使用干扰RNA来促进靶向的，特定的敲低MAP激酶亚型的体内。通过建立良好的技术和更新的技术结合了艺术视网膜功能生理学评估，组织学检查以及细胞死亡和分子机制的表征，我们将使用强大而强大的模型来阐明有希望的方法来诱导视网膜中的内源性神经保护。 公共卫生相关性：结合艺术视网膜功能生理生理学评估，组织学检查以及通​​过良好建立和更新的技术对细胞死亡和分子机制的表征，我们将使用强大而强大的模型来阐明视网膜中诱导内源性神经保护的机制。