Novel Mechanisms of Regenerative Wound Healing

伤口再生愈合的新机制

• 批准号: 9331717
• 负责人: Sundeep G Keswani
• 金额: $ 30.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331717
• 关键词: Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Benchmarking; Biological; Biology; Caring; Cell physiology; Characteristics; Cicatrix; Data; Dermal; Diabetes Mellitus; Disease; Effector Cell; Extracellular Matrix; Fibroblasts; Goals; Hyaluronan; Impaired wound healing; Impairment; In Vitro; Inflammation; Inflammatory Response; Interleukin-10; Knockout Mice; Knowledge; Lead; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Weight; Pathway interactions; Patient Care; Phenotype; Pregnancy; Public Health; Regenerative response; Regulation; Research; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Skin; Source; Stimulus; Surgeon; Testing; Tissues; Transgenic Mice; Wound Healing; clinical practice; clinical translation; fetal; fetal reactivity; healing; immunoregulation; improved; in utero; in vivo; innovation; insight; keratinocyte; migration; mouse model; novel; overexpression; pleiotropism; postnatal; regenerative; repaired; response; therapeutic development; tissue repair; wound

Project Summary Abstract Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired. We can use the biologic basis of the fetal regenerative phenotype as a roadmap to recapitulate regenerative wound healing in adult skin. This would have significant impact for normal wound repair, as well as in impaired wound healing states, such as diabetes. Fetal wounds are characterized by an attenuated inflammatory response and a characteristic fibroblast-mediated ECM, that is composed of high molecular weight hyaluronan. The dermal fibroblast is a primary source of hyaluronan in fetal skin; conversely, in adult wounds, the fibroblast is the main mediator of scar formation. We hypothesize that there are cellular processes in fetal fibroblasts that regulate the regenerative phenotype, which are also present in fibroblasts resident in adult wounds but lack an appropriate stimulus. Our data suggests that interleukin-10 (IL-10) may be the initial stimulus that reactivates a regenerative phenotype in adult wounds. In addition to IL-10's accepted immuno-regulatory role, our preliminary data indicate a new mechanism for IL-10 in the fetal regenerative phenotype and that is regulation of the extracellular matrix, specifically hyaluronan synthesis. To elucidate the mechanisms by which IL-10 governs fetal regenerative healing and to determine whether activation of these same mechanisms in fibroblasts resident in adult wounds can recapitulate regenerative repair, we propose the following three aims: Aim 1: identify and characterize the effects of IL-10 on the fetal fibroblast formation of hyaluronan and elucidate a potential signaling pathway. After testing if this pathway that regulates the ECM is essential to the fetal wound healing phenotype, we can determine if IL-10 induction of hyaluronan synthesis can affect regenerative wound healing in adult wounds. Aim 2: use a series of novel transgenic mice to test if IL-10's effects are mediated via STAT3 dependent signaling in dermal fibroblasts and determine if the fibroblast is the key effector cell of IL-10's regenerative response. Aim 3: test if the IL-10 induced hyaluronan ECM is essential to enhancing cellular functions of the fibroblast and attenuating wound inflammation as part of the regenerative response. Lastly, using mouse models that are characterized by dysfunctional fibroblasts and altered wound inflammation, we will determine if IL-10 can correct these collective deficiencies and augment wound repair. For unknown reasons, the remarkable ability that we all possess to heal regeneratively in utero is lost in late gestation and instead defaults to a scarring phenotype. Completing our aims will yield fundamental insights and new knowledge into IL-10 biology and the recapitulation of fetal regenerative healing in adult wounds. This will offer significant possibilities to improve the care of patients who cope with the debilitating aspects of impaired wound healing quality and scar formation by the development of therapeutics that may have broad implications for regenerative tissue repair.

项目概要摘要 胎儿伤口以再生表型愈合，与周围皮肤无法区分 恢复皮肤完整性。与此基准相比，所有产后伤口愈合都会受到损害。我们可以使用 胎儿再生表型的生物学基础作为概括再生伤口愈合的路线图 成人皮肤。这将对正常伤口修复以及受损伤口产生重大影响 康复状态，例如糖尿病。胎儿伤口的特点是炎症反应减弱， 一种特征性成纤维细胞介导的 ECM，由高分子量透明质酸组成。真皮层 成纤维细胞是胎儿皮肤中透明质酸的主要来源；相反，在成人伤口中，成纤维细胞是主要的 疤痕形成的介质。我们假设胎儿​​成纤维细胞中存在调节细胞过程 再生表型，也存在于成人伤口中的成纤维细胞中，但缺乏再生表型 适当的刺激。我们的数据表明，白细胞介素 10 (IL-10) 可能是重新激活 成人伤口的再生表型。除了 IL-10 公认的免疫调节作用外，我们的 初步数据表明IL-10在胎儿再生表型中的一种新机制，即调节 细胞外基质的合成，特别是乙酰透明质酸的合成。阐明 IL-10 的作用机制 控制胎儿再生愈合并确定这些相同机制是否在 成人伤口中的成纤维细胞可以重现再生修复，我们提出以下三个目标： 目标 1：识别和表征 IL-10 对透明质酸胎儿成纤维细胞形成的影响并阐明 潜在的信号通路。在测试了这条调节 ECM 的通路是否对胎儿至关重要之后 根据伤口愈合表型，我们可以确定 IL-10 诱导透明质酸合成是否会影响再生 成人伤口的伤口愈合。目标 2：使用一系列新型转基因小鼠来测试 IL-10 的作用是否有效 通过真皮成纤维细胞中的 STAT3 依赖性信号传导介导，并确定成纤维细胞是否是关键效应器 IL-10 再生反应的细胞。目标 3：测试 IL-10 诱导的透明质酸 ECM 是否对于 作为再生的一部分，增强成纤维细胞的细胞功能并减轻伤口炎症 回复。最后，使用以成纤维细胞功能失调和伤口改变为特征的小鼠模型 炎症，我们将确定 IL-10 是否可以纠正这些集体缺陷并增强伤口修复。 由于未知的原因，我们所有人都拥有的在子宫内再生愈合的非凡能力在 妊娠晚期，而是默认为疤痕表型。完成我们的目标将产生基本的见解 以及 IL-10 生物学的新知识以及成人伤口中胎儿再生愈合的重述。这 将为改善那些应对衰弱方面的患者的护理提供重要的可能性 可能具有广泛影响的治疗方法的发展损害了伤口愈合质量和疤痕形成 对再生组织修复的影响。