Cadherin-11-cre deleter mouse

摘要 这项拨款申请的目的是验证一种新的小鼠模型，使基因缺失， 致关节炎成纤维细胞样滑膜细胞（FLS）。FLS是局部关节内衬非造血细胞， 在活动性类风湿性关节炎中对关节和骨损伤有显著贡献。这种细胞类型被认为是 作为新疗法的有希望的靶点，以增强对疾病活动的控制和/或避免免疫抑制， 类风湿性关节炎患者。然而，缺乏能够诱导基因缺失的删除小鼠品系， 特别是在FLS及其关键亚群中， 这类细胞在类风湿关节炎中的作用机制，以及验证FLS导向疗法的新靶点。 为了开始解决这一领域的瓶颈，我们已经产生了一种新的删除小鼠品系， 首次实现了由钙粘蛋白-11启动子特异性驱动的基因缺失，钙粘蛋白-11是一种标记细胞凋亡的分子。 在关节炎小鼠和患有类风湿性关节炎的人类中，FLS的侵袭性群体。在目标1中， 提供证据表明，我们的新的cre deleter菌株在FLS和整个过程中选择性表达， 实验性关节炎在目标2中，我们将提供原则证据的证明，即在FLS中cre表达不 影响疾病的严重程度，并且新菌株能够驱动FLS特异性缺失测试基因 据信通过对FLS的作用在关节炎中起作用。 我们的目标是为在FLS领域工作的每个人创造一个重要的共享资源。因此，如果 如果这项资助的研究取得成功，我们将坚定地致力于将模型存放在JAX上， 一旦收集到足够的数据以支持整个RA使用此类所需资源， 研究社区。

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.