Retinal Ischemia-induced MMPs and ganglion cell death

视网膜缺血诱导的 MMP 和神经节细胞死亡

• 批准号: 6370082
• 负责人: Shravan K Chintala
• 金额: $ 3.57万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2001-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6370082
• 关键词: basement membrane; cell death; collagenase; enzyme activity; enzyme biosynthesis; enzyme induction /repression; extracellular matrix; gene targeting; ischemia; laboratory mouse; metalloendopeptidases; retina circulation disorder; retinal ganglion; western blottings

DESCRIPTION (provided by applicant): Retinal ischemia is defined as an arrest of blood flow and reduction of oxygen supply to the retina. Ischemic damage to the retina is a common pathological factor in a number of blinding diseases in humans including central retinal artery and vein occlusions, diabetes, retinopathy of prematurity, and glaucoma to name a few. Although ischemia-induced damage to the retina is known to lead to irreversible loss of ganglion cells, the pathophysiology underlying this process is not clearly understood. The long-term goal of this laboratory is to determine the triggering mechanisms that lead to ganglion cell loss in retinal ischemia because a complete understanding of the disease process will help us in designing preventative strategies to rescue ganglion cells in sight-threatening ischemic retinal diseases. Preliminary findings, using a central retinal ligation model in mice, support the hypothesis that retinal ischemia induces expression of matrix metalloproteinase gelatinase B (MMP-9) by cells in the ganglion cell layer; that MMP-9 mediates degradation of extracellular matrix (ECM) composing of retinal inner limiting membrane (ILM); and that this leads to apoptosis of ganglion cells. Experiments are now proposed to determine (a) the timing and localization of MMPs in the ganglion cell layer, (b) the cell types that synthesize these MMPs in the ganglion cell layer, (c) the role of a particular MMP that leads to ganglion cell loss, (d) the ECM components that are degraded in the ILM, and (e) the neuroprotective effects of MMP inhibition on ganglion cell loss. The proposed studies would not only facilitate our understanding of the mechanisms that underlie ischemia-induced ganglion cell loss in this model system, but in the long-run would also help us in designing neuroprotective strategies to prevent loss of retinal ganglion cells in blinding ischemic retinal diseases.

描述（由申请人提供）：视网膜缺血的定义为骤停 血流减少和视网膜供氧减少。缺血性损伤 视网膜是许多致盲性疾病的常见病理因素 人类，包括视网膜中央动脉和静脉阻塞、糖尿病、 早产儿视网膜病变和青光眼等。虽然 众所周知，缺血引起的视网膜损伤会导致不可逆的视网膜丧失。 神经节细胞，这一过程背后的病理生理学尚不清楚 明白了。该实验室的长期目标是确定 导致视网膜缺血时神经节细胞丢失的触发机制 因为对疾病过程的完整了解将有助于我们 设计预防策略来拯救视力受到威胁的神经节细胞 缺血性视网膜疾病。初步发现，使用中央视网膜 小鼠结扎模型，支持视网膜缺血诱导的假设 基质金属蛋白酶明胶酶 B (MMP-9) 的细胞表达 神经节细胞层； MMP-9 介导细胞外基质的降解 (ECM)视网膜内界膜(ILM)的组成；这导致 导致神经节细胞凋亡。现在建议进行实验以确定（a） 神经节细胞层中 MMP 的时间和定位，(b) 细胞 在神经节细胞层中合成这些 MMP 的类型，(c) 导致神经节细胞损失的特定 MMP，(d) ECM 成分 在 ILM 中被降解，以及 (e) MMP 抑制的神经保护作用 关于神经节细胞损失。拟议的研究不仅有利于我们 了解缺血诱导神经节细胞的机制 这个模型系统中的损失，但从长远来看也将有助于我们设计 防止视网膜神经节细胞丢失的神经保护策略 致盲的缺血性视网膜疾病。