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的一种常用而有效的方法。 尽管免疫抑制治疗在预防急性移植排斥方面是成功的， 实体器官移植的长期存活受到称为移植血管的条件的影响 疾病（GVD），通过该疾病，移植物内的脉管系统变得闭塞。GVD是 由细胞外基质、平滑肌样细胞（SMLC）和免疫球蛋白的沉积组成。 细胞聚集形成阻塞性新生内膜损伤。目前没有治疗方法， 防止或逆转新生内膜积聚;一旦GVD导致移植物失败， 解决办法是再次移植。此外，以前用于研究GVD的动物模型 产生的GVD与临床样本中观察到的不同，这反映了需要 更好地理解模型的局限性。 该领域的一些开放性问题包括：1）起源是什么（捐赠者与接受者）， 导致新生内膜病变的细胞类型，以及2）驱动新生内膜病变的早期事件是什么 最终成为GVD中新生内膜SMLC的细胞的增殖和迁移。 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物（MHC）错配的GVD模型，但最近的工作 表明这些模型与临床GVD有重要的不同-在这些小鼠模型中， 新生内膜细胞可能来自受体，而在临床心脏移植中，GVD 新生内膜细胞主要是移植物衍生的。 最近描述的基于H-Y抗原驱动的GVD血管移植模型 不相容性可以提供对该问题的补救。在这个模型中， (H-Y抗原提供较小的组织相容性错配）允许供体中膜细胞存活， 与临床GVD发病机制中的观察结果相似。虽然这一观察结果对 新模型的相关性，仍然不清楚中膜平滑肌细胞是否来自 供体组织参与血管闭塞，如其他模型所示。 血管损伤这项建议将解决一些基本的发病问题，在这一点上， 模型，特别是观察新生内膜病变的供体与受体来源， 来自移植血管系统的分化成熟平滑肌细胞有助于新生内膜 SMLC，以及对先前确定的集落刺激因子1（CSF 1）/ 集落刺激因子1受体（CSF 1 R）信号通路在这个模型的GVD。

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.