The role of cell death signals in retinal ischemia

描述（由申请人提供）：由于缺血在青光眼、前缺血性视神经病变（AION）、视网膜和脉络膜血管闭塞、糖尿病视网膜病变、早产儿视网膜病变（ROP）和创伤性视神经病变中的作用，视网膜缺血已被广泛研究。因此，研究视网膜缺血的基本机制具有重要的临床意义。在视网膜缺血中，能量消耗导致受影响最严重区域的坏死细胞死亡，而凋亡神经元集中在缺血区域，那里的损伤较轻。组织坏死导致专业吞噬细胞的炎症和毒性激活，而吞噬细胞消除凋亡细胞刺激抗炎和保护因子的合成。因此，组织中不同类型死细胞的结合可以决定吞噬细胞的毒性或保护作用的优势。缺血组织中坏死细胞多于凋亡细胞的优势可以介导缺血组织中额外的炎症应激。我们的初步数据和文献表明，这种炎症应激可能是视网膜缺血后神经元损伤显著增加的原因。我们假设细胞死亡相关的炎症应激对视网膜缺血的病理有统计学意义。这一假设将在一系列实验中得到验证，具体目的如下：1)确定坏死信号优于凋亡信号是否影响视网膜缺血后损伤严重程度的增加；2)确定细胞坏死倾向是否控制视网膜缺血后损伤严重程度的增加；3)确定吞噬细胞与死细胞相互作用在视网膜缺血后损伤加重中的作用。我们的假设的验证将产生一个潜在的新靶点的新药清单，旨在减少视网膜缺血后的损伤。

DESCRIPTION (provided by applicant): Ischemia has been widely studied in the retina, because of its proposed role in glaucoma, anterior ischemic optic neuropathy (AION), retinal and choroidal vessel occlusions, diabetic retinopathy, retinopathy of prematurity (ROP) and traumatic optic neuropathy. Thus studying the basic mechanisms underlying retinal ischemia is of substantial clinical interest. In retinal ischemia, energy depletion leads to necrotic cell death in the most severely affected areas, whereas apoptotic neurons are concentrated in the area of the ischemic territory, where the insult is milder. Necrosis of tissue leads to inflammatory and toxic activation of professional phagocytes, whereas the elimination of apoptotic cells by phagocytes stimulates the synthesis of anti- inflammatory and protective factors. Hence, the combination of different types of dead cells in tissue can determine the predominance of either toxicity or protection derived from phagocytes. The predominance of necrotic over apoptotic cells in ischemic tissue can mediate additional inflammatory stress in ischemic tissue. Our preliminary data and the literature suggest that such inflammatory stress can be responsible for a significantly greater amount of neuronal damage after retinal ischemia. We hypothesize that cell death related inflammatory stress makes a statistically significant contribution to the pathology of retinal ischemia. This hypothesis will be tested in a series of experiments outlined in the following specific aims: 1) To determine whether the predominance of necrotic over apoptotic signals influences the increased severity of post-ischemic damage in the retina; 2) To determine whether the predisposition of cells to necrosis governs the increased severity of post ischemic damage in the retina; 3) To determine the role of phagocyte interactions with dead cells on the increased severity of post-ischemic damage in the retina. Validation of our hypotheses will generate a potentially new list of targets for novel drugs which are aimed at reducing damage following retinal ischemia. PUBLIC HEALTH RELEVANCE: Retinal ischemia is a common cause of visual impairment and blindness. Predisposition to cell death via necrosis or apoptosis as a result of retinal ischemia could mediate inflammatory stress and consequently affect lesion size and the potential for recovery. The studies outlined in the specific aims will provide a better understanding of the effects of necrotic and apoptotic signals in the pathology of retinal ischemia and can stimulate the discovery of innovative strategies to help prevent the loss of vision in patients with ischemic injury.