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FAS L INDUCED APOPTOSIS IN CORNEA TRANSPLANTATION

FAS L 在角膜移植中诱导细胞凋亡

基本信息

批准号：
6951737
负责人：
Patrick M Stuart
金额：
$ 5.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6951737
关键词：
CD95 molecule apoptosis clinical research cornea eye transplantation gene expression homologous transplantation human subject immunosuppression keratoplasty laboratory mouse nonsurgical revascularization organ culture tissue inhibitor of metalloproteinases transplant rejection transplantation immunology

项目摘要

The acceptance rate for corneal transplantation, one of the most common types of transplantation performed, is typically between 80- 90%. The reasons for this remarkably high success rate are undoubtedly related to the unique environment of the eye. The eye is one of several organs that manifests properties of immune privilege. Immune privilege is characterized by altered immune responses as is seen in the case of allografts which display prolonged survival when placed into an immune privileged site. While the exact mechanism responsible for immune privilege in the eye is at yet unknown, it has been shown that it probably relies on multiple factors which work together to protect this vital organ from rampant inflammatory processes. These include the production of immunosuppressive cytokines, the localization of neuropeptides in ocular neurons, the strategic placement of specialized antigen presenting cells, and the induction of systemic immune deviation following antigen presentation in the eye. Additionally, it has recently been found that FasL in the eye kills invading Fas+ cells and is a significant protective mechanism for this organ. Furthermore, we have recently reported that virtually all corneas that fail to express functional FasL are rejected by their allogeneic hosts, a compared to a 50% rejection rate for corneas expressing functional FasL. The present application extends our previous observations that Fas ligand (FasL) plays a critical role in murine corneal allograft acceptance to determining whether increasing the functional expression of FasL on the cornea leads to concomitant increase in acceptance of corneal allografts. To that end we will identify those reagents that increase corneal FasL expression and test whether treatment of corneal allografts with such reagents leads to increased cornea allograft acceptance. We will also determine whether FasL expression and function are altered by the immunological state of the cornea. This will be accomplished by monitoring FasL expression in diseased and damaged human corneas and comparing this to that observed in normal human corneas. In parallel, we will stimulate cornea disease in mice and determine whether, over the course of the disease, there are changes in FasL expression from the initial stages of inflammation to the resolution of disease. Finally, preliminary data suggests that neovascularization of the cornea is effected by the presence or absence of functional FasL. Namely, that mice which do not express functional FasL display neovascularization to a greater extent than do mice with normal FasL. Consequently, we propose studies to better define the role that Fas and FasL play in corneal neovascularization.

角膜移植是最常见的移植类型之一，其接受率通常在80- 90%之间。成功率如此之高的原因无疑与眼睛所处的独特环境有关。眼睛是表现出免疫特权特性的几个器官之一。免疫特权的特点是免疫反应的改变，这在同种异体移植物的情况下可以看到，当放置在免疫特权部位时，其存活时间延长。虽然眼睛免疫特权的确切机制尚不清楚，但研究表明，它可能依赖于多种因素，这些因素共同作用，保护这个重要器官免受猖獗的炎症过程的影响。这些包括免疫抑制细胞因子的产生，眼神经元中神经肽的定位，特化抗原呈递细胞的策略性放置，以及抗原呈递后的系统性免疫偏差的诱导。此外，最近发现眼睛中的FasL杀死入侵的Fas+细胞，是该器官的重要保护机制。此外，我们最近报道，几乎所有不能表达功能性FasL的角膜都被异体宿主排斥，而表达功能性FasL的角膜的排斥率为50%。本应用扩展了我们之前的观察，即Fas配体（FasL）在小鼠角膜异体移植接受中起关键作用，以确定是否增加FasL在角膜上的功能表达会导致角膜异体移植接受度的增加。为此，我们将确定那些增加角膜FasL表达的试剂，并测试用这些试剂治疗角膜异体移植物是否会增加角膜异体移植物的接受度。我们还将确定FasL的表达和功能是否会因角膜的免疫状态而改变。这将通过监测患病和受损人类角膜中的FasL表达并将其与正常人类角膜中的FasL表达进行比较来实现。同时，我们将刺激小鼠的角膜疾病，并确定在疾病的过程中，从炎症的初始阶段到疾病的消退，FasL的表达是否会发生变化。最后，初步数据表明角膜新生血管的形成受到功能性FasL存在与否的影响。也就是说，不表达功能性FasL的小鼠比FasL正常的小鼠表现出更大程度的新生血管。因此，我们提出了更好地定义Fas和FasL在角膜新生血管中的作用的研究。