Cytokine induced abnormal wound healing

描述（由申请人提供）伤口愈合障碍是一个重要的 导致烧伤后过度愈合的临床问题 增生性疤痕和导致慢性伤口的愈合不充分。我们 和其他人已经记录了相对浓度的显着变化， 三种特殊的细胞因子。这些正在改变 生长因子-β、TGF-β、肿瘤坏死因子-α、TNF-α和 白细胞介素-8，IL-8。这些介体以增加的量存在于 异常愈合的伤口，并诱导细胞的变化， 伤口和细胞所在的基质环境。比如我们 显示烧伤疤痕产生的自分泌和旁分泌TGF-β增加 诱导真皮成纤维细胞合成过量的I型和III型胶原 和合同矩阵。TNF-α上调MMP-2和MMP-9， 这两种蛋白酶与伤口慢性化有关。IL-8降低 角质形成细胞复制和成纤维细胞收缩基质的能力。的 本提案的目的是确定这些调解人 调节皮肤细胞和基质之间的相互作用。 实验策略基于两个主要目标。首先，细胞因子诱导 细胞骨架的含量、合成、磷酸化和组织的变化 蛋白质; α-平滑肌肌动蛋白、talin、黏着斑蛋白和α 2 β 1整合素 将使用生物化学和分子生物学方法来表征细胞因子治疗 生物学方法。将特别注意以下方面的作用： Rho/GTPases作为成纤维细胞重组的关键信号系统 矩阵第二，这些细胞因子对诱导、合成和 测定基质金属蛋白酶的活化。我们将分析 - MMP-2和MMP-9的启动子区，用于对细胞因子的应答元件， 单个基质蛋白作为其调节的特定机制。 最后，研究了苦参碱介导的MMPs调节对胶原的影响。 收缩将被记录。这些研究将增加我们对 对马槟榔碱诱导的伤口愈合异常的机制进行了研究。的 该项目的长期目标是揭示潜在的关键机制， 增生性瘢痕可能会导致改善治疗，也许， 预防战略。

DESCRIPTION (provided by applicant) Disordered wound healing is a significant clinical problem resulting in both the exaggerated healing of post-bum hypertrophic scar and the inadequate healing that results in chronic wounds. We and others have documented significant changes in the relative concentration of three particular cytokines in these clinical situations. These are transforming growth factor-beta, TGF-beta, tumor necrosis factor-alpha, TNF-alpha and interleukin-8, IL-8. These mediators are present in increased amounts in abnormally healing wounds and induce changes in the cells that populate the wounds and the matrix environment in which the cells reside. For example, we have shown increased burn scar production of autocrine and paracrine TGF-beta induces dermal fibrob lasts to synthesize excessive Types I and III collagen and contract matrix at an increased rate. TNF-alpha up-regulates both MMP-2 and -9, two proteases which have been linked to wound chronicity. IL-8 decreases keratinocyte replication and the ability of fibroblasts to contract matrix. The Goal of this proposal is to determine the mechanisms whereby these mediators regulate the interactions between skin cells and matrix. The experimental strategy is based on two primary aims. First, cytokine induced changes in content, synthesis, phosphorylation and organization of cytoskeletal proteins; alpha-smooth muscle actin, talin, vinculin, and alpha2Beta1 integrin in response to cytokine treatment will be characterized using biochemical and molecular biologic approaches. Particular attention will be directed to the role of Rho/GTPases as a critical signaling system in fibroblast reorganization of matrix. Second, the effects of these cytokines on the induction, synthesis and activation of matrix metalloproteases will be determined. We will analyze the promoter regions of MMP-2 and -9 for response elements to cytokines and individual matrix proteins as a specific mechanism for their regulation. Finally, the effects of cytokine-mediated modulation of MMPs on collagen contraction will be documented. These studies will increase our understanding for the mechanism of cytokine-induced abnormalities of wound healing. The long-term goal of this project is to uncover key mechanisms underlying hypertrophic scarring that may lead to improved therapeutic and, perhaps, preventive strategies.