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 这项拨款申请的目的是验证一种能够在小鼠体内进行基因删除的新型小鼠模型。 致关节炎成纤维细胞样滑膜细胞（FLS）。 FLS 是局部关节衬里非造血细胞， 显着促进活动性类风湿性关节炎的关节和骨损伤。这种细胞类型被认为是 新疗法的有希望的目标，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，缺乏能够诱导基因删除的删除小鼠品系 特别是在 FLS 及其关键亚群中，这严重限制了我们对 FLS 的理解。 该细胞类型在 RA 中的作用机制，以及 FLS 导向疗法新靶点的验证。 为了开始解决该领域的这一瓶颈，我们培育了一种新型删除小鼠品系，可用于 首次实现了由 cadherin-11 启动子特异性驱动的基因删除，cadherin-11 是一种标记 在患有关节炎的小鼠和患有类风湿性关节炎的人类中，FLS 具有攻击性。在目标 1 中，我们将 提供证据表明我们的新 cre 删除菌株在 FLS 中以及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证明 FLS 中的 cre 表达并不 影响疾病的严重程度，并且新菌株能够驱动 FLS 特异性删除测试基因 据信通过对 FLS 的作用来治疗关节炎。 我们的目标是为 FLS 领域的每个人提供重要的共享资源。因此，如果 由这笔资助资助的研究取得成功，我们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，即可发布 研究社区。