ROLE OF TIMPS AND MMPS IN CORNEAL ULCERATION

本研究的目的是明确特定的MMPs及其天然抑制物TIMPs在溃疡性角膜疾病进展或预防中的生物学意义。这将分别使用PA和碱烧伤引起的感染性和无菌角膜溃疡模型来完成。这些模型的比较使用将确定在疾病病理的许多方面非常相似的每个溃烂过程中是否涉及类似的MMPs或TIMP。在确定涉及的MMPs和/或TIMP后，可以实施合理的治疗，以提供针对参与组织破坏的介质的特定靶点，而不影响其他可能被证明是角膜重塑和修复不可或缺的MMPs/TIMP。在这些研究中，将检验两个假设：假设1：在PA角膜攻击后，特定MMPs的异常调节或过度表达会导致进行性的、不可逆的组织破坏，而适当水平的一个或多个TIMP的表达会导致正常的角膜组织重塑。目标L和2被提出直接检验这一假说。目的：利用青壮年(抵抗型)与老年(易感)近交系小鼠模型，探讨特异性基质金属蛋白酶(MMPs)(MMP8、MMP9和MMP13)在PA角膜感染发病机制中的作用。目的：利用抗性与易感近交系小鼠模型，相似地检测特异性TIMP(TIMP-1和TIMP-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透明度/眼部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及其抑制物的表达的能力。目标3和目标4被用来直接检验这一假说。目的：探讨基质金属蛋白酶-8、-9和-13在近交系小鼠角膜碱烧伤发病机制中的作用。目的：在近交系小鼠中度烧伤和重度烧伤的角膜碱烧伤发病机制中，相似地检测特异性TIMP(TIMP-1和TIMP-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.