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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：
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
项目类别：
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

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.