Colony stimulating factor-1 in graft vascular disease

移植血管疾病中的集落刺激因子-1

基本信息

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
项目类别：
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

项目摘要

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（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 病变的特征是由平滑肌样细胞（SMLC）组成的同心血管内膜增生。和相关的细胞外基质；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物缺血和衰竭。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出新内膜 SMLC 的积累大大减少，这表明 CSF-1，巨噬细胞分化、活化和存活的主要介质，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亚型的 op 小鼠。 CSF-1，作为颈动脉同种异体移植中的供体或受体，我们发现受体中缺乏所有CSF-1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 也会损害新内膜形成；当供体组织单独表达 cs 同种型时，这种减少也完全逆转。由 c-fms 癌基因编码的受体（CSF-1R）以及抗体介导的对该受体的阻断可抑制体外 SMLC 增殖。 CSF-1 在供体和受体来源的细胞表面表达，可以在 GVD 中以局部自分泌/邻分泌方式发挥作用，刺激慢性新内膜 SMLC 增殖并最终导致血管阻塞。 CSF-1 信号在 GVD 发病机制中的作用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。假设并评估它所暗示的治疗机会，我们提出三个目标：首先，我们将确定 CSF-1 驱动 GVD 的基本细胞类型；其次，我们将测试药物 CSF-1R 抑制剂预防和治疗的有效性。小鼠移植模型中 GVD 的消退；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 CSF-1 信号通路在人类 GVD 中表达和激活的证据。 1信号传导促进 GVD 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。