ROLE OF TIMPS AND MMPS IN CORNEAL ULCERATION

拟议研究的目的是确定特异性MMPs及其天然抑制剂TIMPs在溃疡性角膜疾病进展或保护中的生物学意义。这将分别使用PA和碱烧伤诱导的感染性和无菌角膜溃疡模型进行。这些模型的比较使用将确定相似的MMPs或TIMPs是否参与每个溃疡过程，其中疾病病理的许多方面非常相似。在确定相关的MMPs和/或TIMPs后，可以实施合理的治疗，以提供参与组织破坏引发的介质的特异性靶向，而不会影响其他可能证明对角膜重塑和修复不可或缺的MMPs/TIMPs。对于这些研究，将验证两个假设：假设1：在PA角膜攻击后，特定MMPs的异常调节或过度表达导致进行性，不可逆的组织破坏，而一种或多种TIMPs的适当表达水平导致正常的角膜组织重塑。目的1和目的2是为了直接检验这一假设。目的1：利用年轻成年（耐药）和老年（易感）近交系小鼠模型，阐明和表征特异性MMPs （MMP-8、-9和-13）在PA角膜感染发病机制中的作用。目的2：使用耐药和易感的近交系小鼠模型类似地检测特异性timp （TIMP-1和-4）在PA角膜感染发病机制中的作用。假设2：中度和重度碱烧伤后恢复角膜清晰度/眼完整性的能力取决于宿主以促进整体角膜组织重塑的方式适当调节单个MMPs及其抑制剂表达的能力。目的3和目的4是为了直接检验这一假设。目的3：通过中度（恢复角膜清晰度）和重度（角膜穿孔）烧伤，阐明和表征近交系小鼠角膜碱烧伤发病机制中的特异性MMPs （MMP-8， -9和-13）。目的4：以类似的方法检测中度和重度烧伤近交系小鼠角膜碱烧伤发病机制中的特异性timp （TIMP-1和-4）。

The objective of the proposed studies is to define the biological significance of specific MMPs and their natural inhibitors, the TIMPs, in the progression of or protection against ulcerative corneal disease. This will be done using infectious and sterile corneal ulcerative models induced by PA and alkali-burn, respectively. Comparative usage of these models will determine if similar MMPs or TIMPs are involved in each ulcerative process in which many aspects of disease pathology are remarkably similar. After identification of the involved MMPs and/or TIMPs, rational therapies could be implemented to provide specific targeting of the mediators involved in the elicitation of tissue destruction without compromising other MMPs/TIMPs that may prove integral to corneal remodeling and repair. For these studies, two hypotheses will be tested: Hypothesis 1: Following PA corneal challenge, abnormal regulation or excessive expression of specific MMPs results in progressive, irreversible tissue destruction, whereas expression of appropriate levels of one or more of the TIMPs leads to normal corneal tissue remodeling. Aims l and 2 are proposed to directly test this hypothesis. Aim 1: To elucidate and characterize specific MMPs (MMP-8, -9 and -13) in the pathogenesis of PA corneal infection using a young adult (resistant) vs aged (susceptible) inbred mouse model. Aim 2: To similarly examine specific TIMPs (TIMP-1 and -4) in the pathogenesis of PA corneal infection using a resistant vs susceptible inbred mouse model. Hypothesis 2: The ability to restore corneal clarity/ocular integrity following moderate vs severe alkali-burns is dependent upon the hosts' ability to appropriately regulate the expression of individual MMPs and their inhibitors in a manner which promotes overall corneal tissue remodeling. Aims 3 and 4 are proposed to directly test this hypothesis. Aim 3: To elucidate and characterize specific MMPs (MMP-8, -9 and -13) in the pathogenesis of corneal alkaliburn in inbred mice using moderate (restore corneal clarity) vs severe (cornea perforates) burns. Aim 4: To similarly examine specific TIMPs (TIMP-1 and -4) in the pathogenesis of corneal alkali-burn in inbred mice using moderate vs severe burns.