Molecular targets of Corneal Anti-fibrosis

角膜抗纤维化的分子靶点

基本信息

批准号：
8589414
负责人：
ROYCE MOHAN
金额：
$ 37.73万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589414
关键词：
Accounting Afghanistan Alkalies Animals Aniridia Binding Binding Sites Blast Injuries Blindness Bone Marrow Transplantation Breeding Cataract Cell Proliferation Cell Transplantation Cells Chemical Injury Chemicals Cicatrix Clinical Cornea Corneal Injury Corneal Neovascularization Corneal Stroma Cytoskeletal Proteins Desmin Development Disease Down-Regulation Epithelial Eye Infections Eye Injuries Eyedrops FDA approved Facial Injuries Fibroblasts Fibrosis Funding Genetic Glial Fibrillary Acidic Protein Gliosis Goals Grant Health Hematopoietic Homologous Gene Human Injury Intermediate Filament Proteins Intermediate Filaments Investigation Iraq Maps Mediating Modality Modeling Molecular Molecular Models Molecular Target Mus Myofibroblast Oryctolagus cuniculus Pathway interactions Permeability Pharmaceutical Preparations Pharmacology Phenotype Principal Investigator Proteins Recovery Recruitment Activity Role Series Site Smooth Muscle Actin Staining Method Soldier Solubility Stimulus Testing Therapeutic Time Validation Vimentin Work analog angiogenesis aqueous base cell type chemical genetics corneal scar drug development drug discovery high throughput screening improved inhibitor/antagonist innovation insight member migration molecular modeling mouse model neovascularization novel overexpression peripherin pre-clinical programs public health relevance reconstitution research study response small molecule tissue repair wound

项目摘要

DESCRIPTION (provided by applicant): Corneal blindness is the second leading cause of vision loss in the world. The exposed cornea is first to also become involved in ocular infections, chemical or blast injuries, and rapidly develops angiogenesis and fibrosis, which ultimately leads to scarring and corneal blindness. In the US alone, work-related eye injuries account for over 50,000 cases per year, while on the battlefield, US soldiers in Iraq and Afghanistan succumb to eye and face injuries at four times the rate of torso injuries. To tackle the prevailing enigma for angio-fibrotic drugs, we developed a high throughput screening platform for drug discovery, from which was borne out the pluripotent inhibitor withaferin A (WFA). A second innovative discovery, afforded by the chemical genetic approach, illuminated vimentin, a type III intermediate filament (IF) protein, as the binding target of WFA. Molecular modeling studies have unraveled the WFA-binding site in tetrameric vimentin and showed, for the first time, a highly conserved druggable site that is retained in members of type III IFs. This unprecedented molecular insight into IF-protein pharmacology combined with studies on target deficient (Vim KO) mice yielded vimentin as a critical regulator of the fibrotic switch. In this current proposed study, we will investigate the hypothesis that type III IF proteins are druggable targets for corneal anti- fibrosis. We will test three specific aims: (1) Activated corneal resident cells engage the corneal fibrotic switch cells by overexpressing vimentin. We will then validate the molecular mechanism of anti-fibrosis exerted by genetic and pharmacological downregulation of vimentin. Additionally, we plan to rescue mice from the ocular disease Aniridia, by inducing vimentin deficiency in these mice. (2) Investigate the role of desmin expression in corneal tissue repair, and demonstrate that desmin combines with vimentin to exacerbate corneal fibrosis and their coordinate downregulation by genetic or pharmacological means can improve corneal recovery after traumatic injury. (3) Develop WFA analogs with improved solubility for topical ocular treatment. Use of these novel WFA analogs will enhance our understanding of therapeutic modalities for WFA-based drug development and the rational to target type III IFs in corneal fibrosis.

描述（由申请人提供）：角膜失明是世界上视力丧失的第二大原因。暴露的角膜也首先参与眼感染，化学或爆炸损伤，并迅速发展为血管生成和纤维化，最终导致疤痕和角膜失明。仅在美国，与工作有关的眼伤是每年超过50,000例，而在战场上，伊拉克的美国士兵和阿富汗的士兵屈服于眼睛，面临躯干受伤率的四倍。解决现行的谜血管纤维性药物，我们开发了一个高通量筛查平台以发现药物，并从中用大量抑制剂（WFA）证实了多能抑制剂。化学遗传方法，点亮波形蛋白（III型中间丝（IF）蛋白）作为WFA的结合靶标提供的第二次创新发现。分子建模研究已经揭示了四聚体波形蛋白中的WFA结合位点，并首次表明了一个高度保守的可药物位点，该部位保留在III型IFS成员中。这种对IF蛋白药理学的前所未有的分子见解与靶标不足（VIM KO）小鼠的研究相结合，产生了波形蛋白作为纤维化开关的关键调节剂。在当前提出的研究中，我们将研究以下假设：如果蛋白质是可药物的角膜抗纤维化靶标，则III型。我们将测试三个特定目的：（1）激活的角膜驻留细胞通过过表达波形蛋白来吸引角膜纤维化开关细胞。然后，我们将验证波形蛋白的遗传和药理下调施加的抗纤维化的分子机制。此外，我们计划通过诱导这些小鼠的波形蛋白缺乏症来挽救小鼠。（2）研究脱敏表达在角膜组织修复中的作用，并证明Desmin与波形蛋白结合使用，以加剧角膜纤维化及其通过遗传或药理手段的坐标下调，可以改善创伤性损伤后的角膜恢复。（3）开发WFA类似物，具有提高局部眼处理的溶解度。使用这些新型的WFA类似物将增强我们对基于WFA的药物发育的治疗方式的理解，以及在角膜纤维化中靶向III型IFS的合理性。