siRNA Inhibition of Keloid Fibrosis in Fibrin Matrix Skin Equivalent Mouse Models

siRNA 抑制纤维蛋白基质皮肤等效小鼠模型中的瘢痕疙瘩纤维化

• 批准号: 8452052
• 负责人: Paul David Benya
• 金额: $ 29.35万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-02 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452052
• 关键词: Address; Affect; African; Animal Model; Asians; Candidate Disease Gene; Cell Line; Cicatrix; Collagen; Complex; Development; Effectiveness; Exhibits; Fibrin; Fibroblasts; Fibrosis; Functional disorder; Gel; Gene Targeting; Goals; Growth; Health; Heart; Hispanics; Human; Implant; In Vitro; Individual; Injury; Keloid; Kidney; Lesion; Liver Fibrosis; Lung; Mediator of activation protein; Modeling; Pathogenesis; Pathologic; Phenotype; Plasminogen Activator Inhibitor 1; Population; Production; Publishing; RNA Interference; Race; Research; Research Personnel; Role; Skin; Small Interfering RNA; Testing; Therapeutic; Tissues; Validation; base; clinical application; effective therapy; efficacy evaluation; genetic manipulation; in vivo; interest; keratinocyte; knowledge base; mouse model; novel therapeutic intervention; overexpression; prevent; social; therapeutic target; tool; tumor; wound

DESCRIPTION (provided by applicant): Keloids are exuberant, tumor-like skin scars that occur unpredictably after injury to the skin in 10 to 20 % of dark skin races, i.e., people of African, Hispanic, and Asian descents. Currently there is no effective treatment to prevent or control the growth and expansion of keloid lesions, which are grievous to the psycho-social and overall health state of the affected individual. The goal of the proposal is to bridge the fundamental obstacles in keloid research by creating gene-targeted and fibrin matrix skin equivalent mouse models of keloid fibrosis, and assessing a RNA interference therapeutic approach. The plan is based on the long-term research effort of Dr. Tuan and the recent progress in keloid pathogenesis from the collaborative effort of Drs. Tuan and Benya (Multiple/Co-PIs). No animal models of keloid fibrosis currently exist that are applicable to routine testing or accurately reflect the human lesion. Moreover, for the development of knowledge-based therapies and their clinical application for keloids, candidate genes must be validated in vivo in animal models and shown to be responsive to targeted therapeutic treatments in such models. Three specific aims are proposed in this application to address the obstacles. Completion of the specific aims will provide a robust, gene-targeted, keloid-derived, skin equivalent animal model based on a three-dimensional fibrin gel mimic of provisional wound matrix. In addition, our target gene PAI-1, which is overexpressed by keloid fibroblasts and has been identified as causative in collagen accumulation in normal and keloid fibroblasts in vitro (published in Am J Pathol., Nov 2008), will have been validated in vivo as an important mediator of keloid fibrosis, while simultaneously demonstrating efficacy of an RNA interference therapeutic approach. Finally, the genetic manipulation of a normal human fibroblast cell line to mimic keloid fibrosis in the model will provide a substitute for keloid fibroblasts in efficacy evaluation and circumvent the limited supply of keloid tissues for routine testing. We also expect that these results and tools will enhance the rate of discovery research in keloid pathogenesis, furthermore, provide a platform, easily modified, for other investigators to validate target genes of interest in keloid fibrosis and test additional novel therapeutic approaches.

描述（由申请人提供）：酮类是繁殖的，类似肿瘤的皮肤疤痕，在10％至20％的深色皮肤种族中，即非洲人，西班牙裔和亚洲人的衰落后，皮肤受伤后发生了不可预测的。目前尚无有效的治疗方法来预防或控制乳突病变的生长和扩张，这对受影响个体的心理社会和整体健康状况而言是严重的。该提案的目的是通过创建靶向基因的和纤维蛋白基质皮肤等效的乳杆状纤维化小鼠模型，并评估RNA干扰治疗方法来弥合乳突研究中的基本障碍。该计划是基于Tuan博士的长期研究工作以及DRS的协作努力从Keloid发病机理中取得的最新进展。 Tuan和Benya（多个/Co-Pis）。目前没有适用于常规测试或准确反映人病变的乳杆状纤维化动物模型。此外，为了开发基于知识的疗法及其针对Keloids的临床应用，必须在动物模型中在体内验证候选基因，并证明对此类模型中有针对性的治疗疗法有反应。在本申请中提出了三个具体目标以解决障碍。特定目标的完成将提供一个基于三维纤维蛋白凝胶临时伤口基质的稳健，靶向，酮的衍生，皮肤等效动物模型。此外，我们的靶基因pai-1被乳杆状成纤维细胞过表达，并已被确定为在正常和酮酮成纤维细胞体外的胶原蛋白积累（在Am J Pathol。，2008年11月出版）中的胶原蛋白积累中，将在体外被验证，并被视为同时互动的重要核糖纤维中的重要层。最后，在模型中，正常的人成纤维细胞细胞系对模拟乳子纤维化的遗传操纵将为有效性评估中的乳子纤维成纤维细胞提供替代品，并避免了有限的酮组织供应进行常规测试的供应。我们还期望这些结果和工具将提高乳突发病机理中发现的发现率，此外，还提供了一个易于修改的平台，以供其他研究人员验证核苷纤维化中感兴趣的靶基因并测试其他新颖的治疗方法。