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: 9276113
• 负责人: Nicholas E Sibinga
• 金额: $ 51.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276113
• 关键词: Address; Affect; Allografting; Antibodies; Arteriosclerosis; Biology; Biopsy; Blood Circulation; Blood Vessels; Cardiac; Cell Proliferation; Cell Survival; Cell surface; Cells; Characteristics; Chronic; Clinic; Clinical; Coronary artery; Development; Diffuse; Disease; Disease model; Effectiveness; Extracellular Matrix; Failure; Gene Transfer Techniques; Growth Factor; Heart Transplantation; Heart failure; Human; Hyperplasia; Impairment; In Vitro; Intervention; Ischemia; Kidney Failure; Kidney Transplantation; Lesion; Life; Ligands; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Mediator of activation protein; Modeling; Mus; Obstruction; Oncogenes; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Pharmacology; Pre-Clinical Model; Prevention; Procedures; Process; Protein Isoforms; Risk; Role; Savings; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Solid; Source; Surface; Testing; Therapeutic; Tissue Donors; Translating; Transplant Recipients; Transplantation; Transplanted tissue; Vascular Diseases; Vascular Graft; autocrine; base; cell growth; cell type; cellular targeting; clinical practice; cytokine; graft failure; 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）：移植物血管疾病（GVD）是实体器官移植长期成功的最大障碍。GVD病变的特征性表现为由平滑肌样细胞（SMLC）和相关细胞外基质组成的同心血管内膜增生;这种内膜扩张在移植器官的整个血管系统中弥漫性发展，最终限制其动脉管道功能并导致移植物缺血和衰竭。与置于对照受体中的那些相比，置于集落刺激因子-1（CSF- 1，也称为M-CSF）缺陷型骨硬化（OP）小鼠中的实验性同种异体移植物显示出新生内膜SMLC的积聚大大减少，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op小鼠，通过转基因重组表达CSF-1的特异性亚型，作为颈动脉同种异体移植的供体或受体。我们发现，受体中缺乏所有CSF-1显著限制了新生内膜增生，而受体细胞表面表达 (cs)单独的CSF-1足以用于新生内膜扩张。令人惊讶的是，供体组织中缺乏CSF-1也会损害新生内膜形成;当供体组织单独表达cs亚型时，这种减少也完全逆转。新生内膜SMLC表达由c-fms癌基因编码的CSF-1受体（CSF-1 R），抗体介导的该受体阻断剂在体外抑制SMLC增殖。总之，这些发现表明，CSF-1，表达在供体和受体来源的细胞的表面上，可以在GVD中以局部自分泌/分泌的方式起作用，以刺激慢性新生内膜SMLC增殖和最终的血管阻塞。基于这些发现，我们假设CSF-1信号在GVD发病机制中的基本功能不仅在于其刺激经典细胞靶点巨噬细胞的能力，而且还在于其对表达CSF-1 R的新生内膜SMLC的影响。为了验证这一假设并评估其所提示的治疗机会，我们提出了三个目标：首先，我们将鉴定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CSF-1 R药理学抑制剂预防和消退GVD的有效性;第三，我们将检查临床移植组织，包括晚期GVD移植物，以寻找人GVD中CSF-1信号通路表达和激活的证据。这些研究将促进对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，这些靶点可以很容易地转化为临床实践，以减轻移植失败。