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（由适用提供）：移植血管疾病（GVD）是固体器官移植长期成功的最大障碍。 GVD的病变特征在于由平滑肌样细胞（SMLC）和相关的细胞外基质组成的浓缩血管增生。这种内膜扩张的发展遍及移植器官的脉管系统，最终限制了其动脉导管功能，并引起移植缺血和失败。与放置在对照受体中的Neimimimal SMLC相比，放置在菌落刺激因子1（CSF-1，也称为M-CSF）中的实验同种异体移植物显示出了新内膜SMLC的积累大大降低，这表明CSF-1，表明CSF-1，CSF-1，乳突分化，激活，活性，活性，生存的重要作用，具有重要的作用，并且具有重要的作用。在最近的研究中，我们使用了由转基因重组的OP小鼠，以表达CSF-1的特定同工型，作为颈动脉动脉同种异体移植移植中的供体或受体。我们发现受体中缺少所有CSF-1，明显有限的新内膜增生，而受体表面的表达 （CS）仅CSF-1就足以进行新内膜扩张。出乎意料的是，供体组织中缺乏CSF-1也损害了新内膜的形成。当供体组织单独表达CS同工型时，这种还原也完全逆转。 Neinidimal SMLC表达了由C-FMS癌基因编码的CSF-1受体（CSF-1R），该受体的抗体介导的阻断抑制了SMLC增殖的体外。综上所述，这些发现表明，在供体和受体衍生细胞表面表达的CSF-1可以以GVD的局部，自分泌/近二氨酸方式作用，以刺激慢性新生素SMLC增殖和最终的血管目标。基于这些发现，我们假设CSF-1信号在GVD发病机理中的基本功能不仅在刺激其经典细胞靶标，巨噬细胞的能力上，而且还对表达CSF-1R的新源性SMLC的影响。为了检验它建议的这一假设和评估理论的机会，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，我们将测试药理学CSF-1R抑制剂在小鼠移植模型中预防和回归GVD的有效性；第三，我们将检查临床移植组织，包括具有晚期GVD的移植物，以证明人GVD中CSF-1信号通路的表达和激活。这些研究将促进对CSF-1信号如何促进GVD的理解，并评估其作为治疗靶标的潜力，可以轻松地将其转化为临床实践以减轻年级衰竭。