Cadherin-11-cre deleter mouse

Cadherin-11-cre删除小鼠

• 批准号: 10784524
• 负责人: Nunzio Bottini
• 金额: $ 28.69万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-28 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10784524
• 关键词: Cadherin; 11; cre; deleter; mouse

ABSTRACT The objective of this grant application is to validate a novel mouse model enabling gene deletion in arthritogenic fibroblast-like synoviocytes (FLS). FLS are local joint-lining non hematopoietic cells that significantly contribute to joint and bone damage in active rheumatoid arthritis. This cell type is considered as a promising target for novel therapies to enhance control of disease activity and/or spare immunosuppression in patients with rheumatoid arthritis. However, the lack of a deleter mouse strain able to induce gene deletion specifically in FLS and their key subpopulations has been a serious limitation to both our understanding of the mechanism of action of this cell type in RA, and to the validation of novel targets for FLS-directed therapies. To begin addressing this bottleneck in the field, we have generated a novel deleter mouse strain that for the first time enables gene deletions specifically driven by the promoter of cadherin-11, a molecule that marks an aggressive population of FLS both in arthritic mice and humans with rheumatoid arthritis. In Aim 1 we will provide evidence that our new cre deleter strain is expressed selectively in FLS and throughout the course of experimental arthritis. In Aim 2 we will provide proof of principle evidence that cre expression in FLS does not influence severity of disease and that the new strain is able to drive FLS-specific deletion of a test gene believed to operate in arthritis via an action on FLS. Our goal is to generate an important shared resource for everybody working in the FLS field. Thus, if the studies funded by this grant succeed, we are firmly committed to depositing the model at JAX even before publication, as soon as sufficient data are collected to support use of such a needed resource by the whole RA research community.

抽象的 该赠款应用的目的是验证一种新的鼠标模型，从而实现基因缺失 关节炎成纤维细胞样细胞（FLS）。 FL是局部联合衬里非造血细胞， 显着导致活动类风湿关节炎的关节和骨损伤。该单元格被认为是 新型疗法的有希望的靶标，以增强对疾病活动和/或备用免疫抑制的控制 类风湿关节炎患者。但是，缺乏能够诱导基因缺失的deleter小鼠应变 特别是在FL及其关键亚群中，我们对我们对 该细胞类型在RA中的作用机理，以及对FLS定向疗法的新靶标验证。 为了开始解决该领域的这种瓶颈，我们已经产生了一种新颖的Deleter Mouse菌株 第一次启用基因删除是由Cadherin-11的启动子专门驱动的，这是一种标记的分子 在关节炎小鼠和类风湿关节炎的人类中，FL的侵略性人群。在目标1中，我们将 提供证据表明我们的新Cre deleter菌株在FL中有选择地表达 实验性关节炎。在AIM 2中，我们将提供原则证据证明CRE在FLS中的表达不会 影响疾病的严重程度，新菌株能够驱动测试基因的FLS特异性缺失 认为可以通过对FL的作用在关节炎中进行操作。 我们的目标是为在FLS领域工作的每个人生成重要的共享资源。因此，如果是 由这笔赠款资助的研究成功，我们也坚定地将模型存入JAX之前 出版物，一旦收集了足够的数据来支持整个RA的使用此类必要的资源 研究社区。