Colony stimulating factor-1 in graft vascular disease

移植血管疾病中的集落刺激因子-1

• 批准号: 8985741
• 负责人: Nicholas E Sibinga
• 金额: $ 17.49万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985741
• 关键词: Abbreviations; Address; Affect; Allografting; Antibodies; Arteriosclerosis; Biological Assay; Biology; Biopsy; Blood Circulation; Blood Vessels; Cardiac; Cell Proliferation; Cell Survival; Cell surface; Cells; Chronic; Clinic; Clinical; Coronary artery; Development; Disease; Disease model; Effectiveness; Extracellular Matrix; Failure; Gene Transfer Techniques; Growth Factor; Heart Transplantation; Heart failure; Human; Hyperplasia; In Situ Hybridization; In Vitro; Interferons; Interleukins; Intervention; Ischemia; Kidney; Kidney Failure; Lesion; Life; Ligands; Ligation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Major Histocompatibility Complex; Mediating; Mediator of activation protein; Modeling; Mus; Myosin Heavy Chains; Nitric Oxide Synthase; Obstruction; Oncogenes; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Platelet-Derived Growth Factor; Pre-Clinical Model; Prevention; Procedures; Process; Protein Isoforms; Relative (related person); Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Smooth Muscle Myosins; Solid; Source; Staging; Surface; TNF gene; Testing; Therapeutic; Tissue Donors; Transforming Growth Factors; Translating; Transplant Recipients; Transplantation; Transplanted tissue; Tumor Necrosis Factor-alpha; Vascular Diseases; autocrine; base; c-fms Proto-Oncogenes; cell growth; cell type; cellular targeting; clinical practice; cytokine; graft failure; human MYH11 protein; inhibitor/antagonist; macrophage; migration; mouse model; neointima formation; novel; novel strategies; pre-clinical; prevent; public health relevance; receptor; reconstitution; success; therapeutic target; transdifferentiation

 DESCRIPTION (provided by applicant): Graft vascular disease (GVD) is the single greatest barrier to the long-term success of solid-organ transplantation. The lesions of GVD characteristically show concentric vascular intimal hyperplasia composed of smooth muscle-like cells (SMLCs) and associated extracellular matrix; this intimal expansion develops diffusely throughout the vasculature of transplanted organs, eventually limiting their arterial conduit function and causing graft ischemia and failure. Experimental allografts placed in Colony Stimulating Factor-1 (CSF- 1, also known as M-CSF)-deficient osteopetrotic (op) mice show greatly reduced accumulation of neointimal SMLCs compared to those placed in control recipients, suggesting that CSF-1, the principal mediator of macrophage differentiation, activation, and survival, has a significant role in GVD. In recent studies, we used op mice, reconstituted by transgenesis to express specific isoforms of CSF-1, as either donors or recipients in carotid arterial allograft transplantation. We found that lack of all CSF-1 in recipients significantly limited neointimal hyperplasia, while recipient expression of cell surface (cs) CSF-1 alone was sufficient for neointimal expansion. Surprisingly, absence of CSF-1 in donor tissue also impaired neointima formation; this reduction was also completely reversed when donor tissue expressed the cs isoform alone. Neointimal SMLCs expressed the CSF-1 receptor (CSF-1R) encoded by the c-fms oncogene, and antibody-mediated blockade of this receptor inhibited SMLC proliferation in vitro. Taken together, these findings suggest that CSF-1, expressed on the surface of both donor and recipient derived cells, can act in a local, autocrine/juxtacrine manner in GVD to stimulate chronic neointimal SMLC proliferation and eventual vascular obstruction. Based on these findings, we hypothesize that an essential function of CSF-1 signaling in GVD pathogenesis resides not only in its ability to stimulate its classical cellular target, the macrophage, but also in its effects on neointimal SMLCs that express the CSF-1R. To test this hypothesis and assess therapeutic opportunities that it suggests, we propose three aims: first, we will identify the essential cell type(s) through which CSF-1 drives GVD; second, we will test the effectiveness of pharmacologic CSF-1R inhibitors for prevention and regression of GVD in mouse transplantation models; and third, we will examine clinical transplant tissues, including grafts with advanced GVD, for evidence of expression and activation of the CSF-1 signaling pathway in human GVD. These studies will advance understanding of how CSF-1 signaling promotes GVD and evaluate its potential as a therapeutic target that can be readily translated into clinical practice to mitigate graft failure.

 描述（由申请人提供）：移植血管疾病（GVD）是实体器官移植长期成功的最大障碍。 GVD的病变特征为由平滑肌样细胞（SMLC）和相关细胞外基质组成的同心圆血管内膜增生；这种内膜扩张在移植器官的脉管系统中广泛发展，最终限制其动脉导管功能并导致移植器官缺血和衰竭。与放置在对照受体中的移植物相比，放置在集落刺激因子-1（CSF-1，也称为 M-CSF）缺陷的骨硬化（op）小鼠中的实验性同种异体移植物显示，新内膜 SMLC 的积累大大减少，这表明 CSF-1 作为巨噬细胞分化、激活和存活的主要介质，在 GVD 中具有重要作用。在最近的研究中，我们使用通过转基因重组来表达特定 CSF-1 亚型的 op 小鼠作为颈动脉同种异体移植中的供体或受体。我们发现，受体中所有 CSF-1 的缺乏显着限制了新内膜增生，而受体细胞表面的表达 (cs) 单独的 CSF-1 足以进行新内膜扩张。令人惊讶的是，供体组织中缺乏 CSF-1 也会损害新内膜的形成；当供体组织单独表达cs亚型时，这种减少也完全逆转。新内膜 SMLC 表达由 c-fms 癌基因编码的 CSF-1 受体 (CSF-1R)，抗体介导的对该受体的阻断可抑制 SMLC 体外增殖。总而言之，这些发现表明，在供体和受体衍生细胞表面表达的 CSF-1 可以在 GVD 中以局部自分泌/近分泌方式发挥作用，刺激慢性新内膜 SMLC 增殖并最终导致血管阻塞。基于这些发现，我们假设 CSF-1 信号传导在 GVD 发病机制中的重要功能不仅在于其刺激其经典细胞靶标巨噬细胞的能力，还在于其对表达 CSF-1R 的新内膜 SMLC 的影响。为了检验这一假设并评估它所暗示的治疗机会，我们提出了三个目标：首先，我们将确定 CSF-1 驱动 GVD 的基本细胞类型；其次，我们将在小鼠移植模型中测试药理学CSF-1R抑制剂预防和消退GVD的有效性；第三，我们将检查临床移植组织，包括晚期 GVD 的移植物，以寻找人类 GVD 中 CSF-1 信号通路表达和激活的证据。这些研究将加深对 CSF-1 信号传导如何促进 GVD 的理解，并评估其作为治疗靶点的潜力，该治疗靶点可以轻松转化为临床实践以减轻移植失败。