Role of colony stimulating factor 1 receptor (CSF1R) in graft vascular disease

项目摘要 实体器官移植是治疗终末期器官衰竭常见而有效的方法。 虽然免疫抑制治疗在预防急性移植物排斥反应方面取得了成功， 实体器官移植的长期存活受到一种称为移植物血管的疾病的影响。 疾病(GVD)，移植物内的血管系统被闭塞。GVD是 由细胞外基质沉积、平滑肌样细胞和免疫组成 积聚形成梗阻性新生内膜病变的细胞。目前还没有治疗方法 防止或逆转新的内膜堆积；一旦GVD导致移植失败，最终的 解决办法是再次移植。此外，以前用于研究GVD的动物模型已经 产生的GVD与临床样本中观察到的不同，这反映了需要 以更好地理解这些模型的局限性。 该领域的一些悬而未决的问题包括1)来源是什么(捐赠者与接受者)以及 导致新生内膜病变的细胞类型，以及2)哪些早期事件推动了 在GVD中，细胞的增殖和迁移最终成为新的内膜SMLC。 研究人员试图用小鼠血管移植来回答这些问题 主要组织相容性复合体(MHC)错配的GVD模型，但最近的工作 这表明这些模型与临床GVD有很大不同--在这些小鼠模型中， 新的内膜细胞可能来自受体，而在临床心脏移植中，GVD 新生内膜细胞多为移植物来源。 一种基于H-Y抗原驱动的GVD血管移植模型 不兼容可能会为这个问题提供补救措施。在这个模型中，较温和的组织不相容 (H-Y抗原提供较小的组织相容性不匹配)允许供体中间细胞存活， 与临床观察到的GVD发病机制相似。虽然这一观察结果对 与新模型的相关性，目前仍不清楚中膜平滑肌细胞是否来自 供体组织参与了血管闭塞，正如其他模型所显示的那样 血管损伤。这项建议将解决一些基本的病因学问题 模型，特别关注供体和受体新生内膜病变的来源，在多大程度上 移植血管分化成熟的平滑肌细胞有助于新生内膜的形成 SMLC，以及对先前已确定的集落刺激因子1(CSF1)的需求。 GVD模型中集落刺激因子1受体(CSF1R)信号转导途径的研究

Project Summary Solid organ transplantation is a common and effective treatment of end-stage organ failure. Although immunosuppressive treatment has been successful in preventing acute graft rejection, the long-term survival of solid organ transplants is affected by a condition termed graft vascular disease (GVD), through which the vasculature within the graft becomes occluded. GVD is composed of deposition of extracellular matrix, smooth muscle-like cells (SMLCs) and immune cells that accumulate to form obstructive neointimal lesions. Currently there is no treatment to either prevent or reverse neointimal accumulation; once GVD leads to graft failure, the ultimate solution is to retransplant. Furthermore, animal models previously used to study GVD have produced GVD that differs from what is observed in clinical samples, which reflects on the need to better understand the limitations of the models. Some of the open questions in the field include 1) what are the origins (donor vs recipient) and cell types that contribute to neointimal lesions, and 2) what are the early events that drive the proliferation and migration of cells that eventually become neointimal SMLCs in GVD. Investigators have attempted to answer these questions using murine vascular transplant models of GVD with Major Histocompatibility Complex (MHC) mismatches but recent work suggests that these models differ importantly from clinical GVD — in these mouse models, neointimal cells may arise from the recipient, whereas in clinical heart transplantation, GVD neointimal cells are mostly graft derived. A recently described vascular transplant model of GVD based on H-Y antigen-driven incompatibility may provide a remedy to this problem. In this model, milder tissue incompatibility (H-Y antigens provide minor histocompatibility mismatch) allows survival of donor medial cells, similar to observations in clinical GVD pathogenesis. While this observation is promising for the relevance of the new model, it is still not clear whether medial smooth muscle cells from the donor tissue are participating in vascular occlusion, as has been shown in other models of vascular injury. This proposal will address some of these basic pathogenetic questions in this model, specifically looking at donor vs recipient origin of neointimal lesions, the extent to which differentiated mature smooth muscle cells from the graft vasculature contribute to neointimal SMLCs, and the requirement for the previously identified colony stimulating factor 1 (CSF1)/ colony stimulating factor 1 receptor (CSF1R) signaling pathway in this model of GVD.