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ROLE OF TIMPS AND MMPS IN CORNEAL ULCERATION

TIMPS 和 MMPS 在角膜溃疡中的作用

基本信息

批准号：
6708857
负责人：
KAREN A KERNACKI
金额：
$ 19.24万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2005-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6708857
关键词：
bacterial disease basement membrane biochemistry burns collagenase cornea ulcer enzyme activity eye infections eye injury eye regeneration histopathology laboratory mouse northern blottings pathologic process tissue inhibitor of metalloproteinases western blottings

项目摘要

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.

拟议研究的目的是确定特定MMPs及其天然抑制剂TIMPs在溃疡性角膜疾病进展或预防中的生物学意义。这将使用分别由PA和碱烧伤诱导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是否相似的MMP或TIMP参与每个溃疡过程，其中疾病病理学的许多方面非常相似。在鉴定所涉及的MMP和/或TIMP后，可以实施合理的治疗以提供参与组织破坏的诱发的介质的特异性靶向，而不损害可能被证明与角膜重塑和修复不可或缺的其他MMP/TIMP。对于这些研究，将检验两个假设：假设1：PA角膜激发后，特定MMP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TIMP的适当水平的表达导致正常角膜组织重塑。目的1和2提出直接测试这一假设。目标1：使用年轻成年（抗性）与老年（敏感）近交系小鼠模型阐明和表征PA角膜感染发病机制中的特异性MMP（MMP-8、MMP-9和MMP-13）。目标二：使用耐药与敏感近交系小鼠模型，类似地检查PA角膜感染发病机制中的特异性TIMP（TIMP-1和TIMP-4）。假设二：中度与重度碱烧伤后恢复角膜透明度/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个体MMP及其抑制剂表达的能力。目的3和4是为了直接检验这一假设。目标三：使用中度（恢复角膜透明度）与重度（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MMP（MMP-8、MMP-9和MMP-13）。目的4：用中、重度角膜碱烧伤近交系小鼠，研究角膜碱烧伤发病机制中特异性TIMP-1和TIMP-4的表达。