CHEMOKINES AND IMMUNE CELLS IN HIND LIMB ISCHEMIA

后肢缺血中的趋化因子和免疫细胞

基本信息

批准号：
7622550
负责人：
PAULA K SHIREMAN
金额：
$ 37.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7622550
关键词：
Ablation Adipocytes Adjuvant Adjuvant Therapy Afghanistan Amputation Animals Arteries Biological Assay Biological Response Modifiers Biology Blood Vessels Blood capillaries Bone Marrow Bone Marrow Cells CC chemokine receptor 2 Cells Chest Chimera organism Complex Defect Deposition Development Direct Lytic Factors Dissection Endothelial Cells Excision Exclusion Exhibits Fatty acid glycerol esters Fibrosis Fluorescence Genotype Goals Grant Green Fluorescent Proteins Healed Hematopoietic Immune Immune response Immunology Impairment Inflammation Inflammatory Injection of therapeutic agent Injury Ischemia Knockout Mice Lead Leg Limb Salvage Limb structure Mediating Modeling Monocyte Chemoattractant Protein-1 Mus Muscle Natural regeneration Necrosis Outcome Pathology Patients Peripheral Phenotype Physiology Play Predisposition Production Proteins Radiation Chimera Research Role Skeletal Muscle Skeletal muscle injury Smooth Muscle Myocytes Soldier Source System T-Lymphocyte Testing Time Tissue Engineering Tissues Transgenic Mice Transgenic Organisms Trauma Upper arm Vascular Endothelial Growth Factors Veterans War Wild Type Mouse Wound Healing angiogenesis capillary cell type chemokine chemokine receptor defined contribution density design femoral artery healing improved in vivo injured innovation irradiation limb injury macrophage matrigel monocyte mouse model muscle regeneration novel older patient progenitor receptor regenerative research study response restoration soft tissue stem cell biology success tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Muscle regeneration and angiogenesis are important components of limb salvage following traumatic and/or ischemic injury to the extremities. We have demonstrated that knockout mice lacking either monocyte chemotactic protein-1 (MCP-1) or its specific receptor, the CC Chemokine Receptor 2 (CCR2), have impairments in macrophage recruitment and muscle regeneration following ischemic or toxic injury. In addition, CCR2-/- mice exhibit increased adipocyte accumulation in regenerated muscle. Bone marrow (BM) replacement of CCR2 -/- mice with wild type (WT) BM (radiation chimeras) led to increased early macrophage recruitment and normal muscle regeneration (i.e., recapitulated the phenotype of WT mice). Furthermore, replacing the BM of WT mice with CCR2 -/- BM resulted in decreased macrophage recruitment and impaired muscle regeneration (i.e., recapitulated the phenotype of CCR2 -/- mice). This suggests that BM-derived cells modulate the healing responses of muscle and that macrophages are the likely BM-derived cell type that mediates the impaired muscle regeneration in CCR2 -/- mice. Further studies revealed impaired angiogenesis in CCR2 -/- mice in conjunction with decreased tissue vascular endothelial growth factor (VEGF) compared to WT mice. Interestingly, restoration of VEGF to baseline levels was associated with the development of maximal capillary density in both CCR2 -/- and WT mice. While impaired muscle regeneration in CCR2 -/- mice is attributable to a BM-derived cell, the effects of BM-derived vs. host-derived cells have not been studied in regards to angiogenesis. Our long-term goal is to define the influence of inflammation, including the chemokine system, in angiogenesis and skeletal muscle regeneration. The following 3 specific aims will test the overall hypothesis that the recruitment and activation of BM-derived cells, especially monocytes/macrophages, are essential for angiogenesis, a critical component in skeletal muscle regeneration after injury. 1) Determine the contribution of CCR2 expression in BM-derived vs. non-BM- derived cells on angiogenesis in skeletal muscle after injury, 2) Determine the ex vivo and in vivo influence of the MCP-1/CCR2 axis on angiogenesis and 3) Define the effects of selective and complete monocyte/macrophage ablation prior to muscle injury and sustained throughout the time course of tissue repair on inflammation and angiogenesis after injury. The proposed studies are innovative because they will help define the contribution of BM-derived cells to angiogenesis. The significance of this research is that a better understanding of the mechanisms of skeletal muscle regeneration and angiogenesis could lead to the design of novel primary or adjuvant treatments for improved limb salvage and tissue engineering. PUBLICE HEALTH RELEVANCE: Leg and arm wounds, with large muscle defects and high amputation rates, are common in trauma victims and especially in injured soldiers from the Iraqi/Afghanistan war; new treatments to replace the missing muscle are needed to decrease amputation rates and improve limb function. Our research studies the complex relationships between the multiple cells that are needed to make new muscle, including blood vessels. A better understanding of how new blood vessels help muscle recover from injury could lead to new therapies, including tissue engineering strategies, to help patients recover from these devastating injuries.

描述（由申请人提供）：肌肉再生和血管生成是四肢创伤和/或缺血性损伤后保肢的重要组成部分。我们已经证明，缺乏单核细胞趋化蛋白-1 (MCP-1) 或其特异性受体 CC 趋化因子受体 2 (CCR2) 的基因敲除小鼠，在缺血或中毒性损伤后巨噬细胞募集和肌肉再生方面会受到损害。此外，CCR2-/-小鼠在再生肌肉中表现出脂肪细胞积累增加。用野生型 (WT) BM（放射嵌合体）替代 CCR2 -/- 小鼠的骨髓 (BM) 导致早期巨噬细胞募集增加和正常肌肉再生（即重现 WT 小鼠的表型）。此外，用 CCR2 -/- BM 替换 WT 小鼠的 BM 会导致巨噬细胞募集减少和肌肉再生受损（即重现 CCR2 -/- 小鼠的表型）。这表明骨髓来源的细胞调节肌肉的愈合反应，并且巨噬细胞可能是介导 CCR2 -/- 小鼠受损肌肉再生的骨髓来源的细胞类型。进一步的研究表明，与 WT 小鼠相比，CCR2 -/- 小鼠的血管生成受损，并且组织血管内皮生长因子 (VEGF) 减少。有趣的是，在 CCR2 -/- 和 WT 小鼠中，VEGF 恢复至基线水平与最大毛细血管密度的发展相关。虽然 CCR2 -/- 小鼠的肌肉再生受损可归因于 BM 衍生细胞，但尚未研究 BM 衍生细胞与宿主衍生细胞对血管生成的影响。我们的长期目标是确定炎症（包括趋化因子系统）对血管生成和骨骼肌再生的影响。以下 3 个具体目标将检验总体假设，即骨髓衍生细胞（尤其是单核细胞/巨噬细胞）的招募和激活对于血管生成至关重要，而血管生成是损伤后骨骼肌再生的关键组成部分。 1) 确定 BM 衍生细胞与非 BM 衍生细胞中 CCR2 表达对损伤后骨骼肌血管生成的贡献，2) 确定 MCP-1/CCR2 轴对血管生成的体外和体内影响，以及 3 ）定义肌肉损伤前选择性和完全单核细胞/巨噬细胞消融以及在组织修复过程中持续的对损伤后炎症和血管生成的影响。拟议的研究具有创新性，因为它们将有助于确定骨髓来源的细胞对血管生成的贡献。这项研究的意义在于，更好地了解骨骼肌再生和血管生成的机制可能有助于设计新的主要或辅助治疗，以改善保肢和组织工程。公共健康相关性：腿部和手臂伤口具有较大的肌肉缺陷和较高的截肢率，在创伤受害者中很常见，特别是在伊拉克/阿富汗战争中受伤的士兵中；需要新的治疗方法来替代缺失的肌肉，以降低截肢率并改善肢体功能。我们的研究研究了制造新肌肉（包括血管）所需的多个细胞之间的复杂关系。更好地了解新血管如何帮助肌肉从损伤中恢复可能会带来新的疗法，包括组织工程策略，以帮助患者从这些毁灭性损伤中恢复。