Role(s) of VEGF in Resolution of Inflammation

VEGF 在炎症消退中的作用

基本信息

批准号：
7846546
负责人：
MANUELA M. MARTINS-GREEN
金额：
$ 3.96万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-19 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846546
关键词：
Address Affect Agonist Apoptosis Area Cell Death Cells Cessation of life Chronic Clinical Trials Collaborations Complex Coupled Development Enzyme-Linked Immunosorbent Assay Event Funding Granulation Tissue Growth Factor Head Healed Health Histology Human Hypersensitivity Immunity Immunologic Techniques Immunology Impaired wound healing Inflammation Inflammatory Inflammatory Response Investigation Knowledge Lead Length Letters Leukocytes Mediating Mediator of activation protein Medical Modeling Mus Pathway interactions Phase Physiological Processes Process Production Resolution Reverse Transcriptase Polymerase Chain Reaction Role Site Small Interfering RNA T-Lymphocyte TNF gene Technology Testing Time Tissues Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Wild Type Mouse Work Wound Healing angiogenesis cell type cytokine healing improved in vivo macrophage member novel novel strategies receptor tumor tumor growth wound

项目摘要

PROJECT SUMMARY Inflammation is a key process in normal wound repair. Upon wounding, cytokines are activated and chemoattract leukocytes, including macrophages, to the wound site. Macrophages are key for the proper formation of granulation tissue because they clean up dead cells in the wound and produce a plethora of cytokines that initiate formation of the healing tissue. While many detailed mechanisms involved early in inflammation are known, those involved in resolution of inflammation are poorly understood. Understanding how inflammation ends is as important as understanding its beginning because prolongation of inflammation leads to impaired healing and chronic inflammatory conditions. VEGF is a key factor in wound healing and is primarily known for its role in angiogenesis. However, recently VEGF is emerging as a regulator of immunity and inflammation. We have discovered that VEGF contributes to resolution of macrophage- induced inflammation during wound healing and that it stimulates macrophage apoptosis in culture. We have also shown that VEGF stimulates the expression of TNFSF14/LIGHT in human macrophages. LIGHT is a member of the TNF superfamily of cytokines known to regulate co-stimulation of T cells as well as apoptosis in mucosal tumors. Our findings point to a novel cytokine-modulated pathway involved in resolution of the inflammatory response. In the work proposed here we address the consequences of these newly discovered functions of VEGF in resolution of inflammation during wound healing. We hypothesize that a novel function of VEGF in the healing process is modulation of macrophage survival in the damaged tissue and that LIGHT is a critical mediator of this process. Specifically, we will: (1) Determine whether VEGF induces macrophage apoptosis in vivo and stimulates LIGHT expression during healing and (2) Determine the relationship between VEGF-induced macrophage cell death and LIGHT. We will use a combination of cultured human macrophages, normal and genetically-modified mice, coupled with agonists/antagonists of VEGF- and LIGHT-dependant pathways. Histochemical and immunological techniques, ELISA, multiplex RT-PCR and siRNA technology will be used. The work proposed is novel because it reveals previously unknown functions of VEGF and it is important because it may facilitate the development of new therapies for poorly-healing wounds as well as other conditions characterized by excessive inflammation and for tumors in which VEGF is upregulated. Because resolution of inflammation occurs poorly or not at all in most abnormal healing situations, this line of investigation is significant for health because it identifies a novel strategy for improving impaired healing, a critical medical area.

项目摘要炎症是正常伤口修复的关键过程。受伤后，细胞因子被激活和趋化的白细胞（包括巨噬细胞）到伤口部位。巨噬细胞是关键为了正确形成肉芽组织，因为它们清理了伤口中的死细胞并产生大量启动愈合组织形成的细胞因子。而很多已知炎症早期涉及的详细机制，涉及分辨率的机制炎症知之甚少。了解炎症的结局与了解其开始，因为炎症的延长会导致治愈受损和慢性炎症条件。 VEGF是伤口愈合的关键因素，主要是已知的因为它在血管生成中的作用。但是，最近VEGF正在成为免疫力调节剂和炎症。我们发现VEGF有助于解决巨噬细胞 - 在伤口愈合过程中诱导炎症，并刺激巨噬细胞凋亡文化。我们还表明，VEGF刺激TNFSF14/Light的表达人类巨噬细胞。光是已知的细胞因子TNF超家族的成员调节粘膜肿瘤中T细胞的共刺激以及凋亡。我们的发现指出一种新型的细胞因子调节途径，参与炎症反应的分辨率。在在这里提出的工作我们解决了这些新发现的功能的后果 VEGF在伤口愈合过程中解决炎症。我们假设这是一本小说 VEGF在愈合过程中的功能是巨噬细胞存活的调节组织和光是该过程的关键中介。具体来说，我们将：（1）确定 VEGF是否在体内诱导巨噬细胞凋亡并刺激光表达在愈合期间和（2）确定VEGF诱导的巨噬细胞之间的关系细胞死亡和光。我们将结合培养的人类巨噬细胞，正常和遗传改性的小鼠，与VEGF和光依赖物的激动剂/拮抗剂结合途径。组织化学和免疫学技术，ELISA，多重RT-PCR和siRNA 技术将被使用。提出的工作是新颖的，因为它揭示了以前未知的 VEGF的功能很重要，因为它可能有助于开发新疗法用于治疗良好的伤口以及其他以过度炎症为特征的疾病对于VEGF上调的肿瘤。因为炎症的分辨率很差在大多数异常愈合情况下，这一调查方面对健康很重要因为它确定了改善康复受损的新策略，这是一个关键的医疗领域。