The regulatory roles of type III collagen in cutaneous wound healing

III型胶原蛋白在皮肤伤口愈合中的调节作用

• 批准号: 10474403
• 负责人: SUSAN W VOLK
• 金额: $ 40.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474403
• 关键词: Adult; American; Architecture; Attenuated; Binding; Biochemical; Biocompatible Materials; Biological Availability; Biophysical Process; Biophysics; Cells; Characteristics; Chronic; Chronic Disease; Cicatrix; Clinical; Collagen; Collagen Fiber; Collagen Fibril; Collagen Type I; Collagen Type III; Communication; Complement Factor B; Cysteine; Data; Deposition; Dermal; Dermis; Development; Disease; Environment; Epithelial Cells; Equilibrium; Evolution; Extracellular Matrix; Extracellular Matrix Proteins; Fetus; Fibrillar Collagen; Fibroblasts; Future; Goals; Granulation Tissue; Growth Factor; Health; Health Care Costs; Health Expenditures; Human; Impaired healing; Impairment; In Vitro; Inferior; Injury; Integrins; Intervention; Lead; Liver Cirrhosis; Mammals; Mechanics; Mediating; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Natural regeneration; Normal tissue morphology; Outcome; Pathologic; Pathology; Persons; Play; Process; Property; Publishing; Pulmonary Fibrosis; Regenerative response; Regulation; Resistance; Role; Science; Signal Transduction; Skin; Skin injury; Skin wound healing; Structure; Testing; Therapeutic; Tissues; Transforming Growth Factors; United States; Wound models; antifibrotic treatment; base; cell motility; chronic wound; crosslink; cytokine; density; experimental study; functional disability; healing; improved; in vivo; innovation; keratinocyte; kidney fibrosis; mechanical properties; migration; neovascularization; non-healing wounds; novel; novel therapeutics; organizational structure; porcine model; pre-clinical; prevent; psychosocial; regenerative; repaired; response; response to injury; restoration; skin regeneration; skin wound; spatiotemporal; viscoelasticity; wound; wound healing; wound response

Abnormal wound healing responses, which include both chronic non-healing wounds and excessive dermal scarring, result in significant morbidity and healthcare expenditures in the United States and worldwide. The extracellular matrix (ECM) plays a critical role in wound repair through regulation of cell migration, differentiation, proliferation, and survival, as well as bioavailability of growth factors. Although type III collagen (Col3), a component of the ECM, is assumed to play an important role in wound repair due to its increased expression early in this process, its precise role has remained enigmatic. Our studies indicate that Col3 has a key role in wound healing, distinct from type I collagen (Col1). Specifically, our in vitro and in vivo published and preliminary data provide evidence that Col3 regulates reparative cell activities and fate by 1) altering ECM organization and structure to direct mechanical communication between cells and the matrix; 2) promoting keratinocyte migration to improve reepithelialization; and 3) limiting scar formation by suppressing the differentiation and persistence of myofibroblasts, the fibrogenic cells of the wound. Additional preliminary data support that Col3 suppresses myofibroblast differentiation via 4) binding and sequestering the profibrogenic cytokine transforming growth factor β (TGFβ) through its N-propeptide, and 5) altering integrin function. The central hypothesis of this proposal is that Col3 directs reparative cell activities and fate to maximize a regenerative response following cutaneous injury. Our goal is to define the structural and cellular mechanisms of Col3, and to demonstrate the efficacy of Col3-containing biomaterials to enhance a regenerative response during wound healing. We propose to accomplish this goal through three major aims: to determine the impact of Col3 on the collagen fibrous network to modulate collagen fibril characteristics, covalent intermolecular cross-linking, and viscoelastic properties during scar evolution and to direct keratinocyte migration (Aim 1), to determine the role of Col3 in the differentiation and persistence of fibrogenic myofibroblasts, specifically its impact on integrin signaling and profibrotic growth factor availability (Aim 2), and to demonstrate the potential for exogenous Col3 to rejuvenate healing in an impaired murine wound healing model and to limit scar formation following cutaneous injury in a preclinical porcine model (Aim 3). Improving our understanding of how Col3 directs a regenerative response during cutaneous wound repair has the potential to identify new anti-fibrotic therapies for other pathologies such as pulmonary and renal fibrosis and hepatic cirrhosis; our third aim will also enable us to apply our findings more immediately to a translatable and safe intervention to treat debilitating chronic wounds and minimize pathologic scarring. As such, we anticipate it will have a significant impact on human health.

伤口愈合反应异常，包括慢性未愈合伤口和过度 皮肤疤痕，在美国导致显著的发病率和医疗支出， 全世界。细胞外基质(ECM)通过调节细胞在创伤修复中发挥重要作用。 迁移、分化、增殖和存活，以及生长因子的生物利用度。虽然 III型胶原(Col3)是细胞外基质的一种成分，被认为在伤口修复中发挥重要作用 由于它在这个过程的早期增加了表达，它的确切作用仍然是个谜。我们的研究 提示COL3在伤口愈合中起关键作用，有别于I型胶原(COL1)。具体来说， 我们在体外和体内发表的和初步的数据提供了证据，证明COL3调节修复 通过1)改变细胞外基质的组织和结构来指导机械通讯的细胞活动和命运 细胞和基质之间；2)促进角质形成细胞迁移，促进再上皮化；3) 通过抑制肌成纤维细胞的分化和持久性来限制瘢痕的形成 伤口的细胞。更多初步数据支持COL3抑制肌成纤维细胞分化 通过4)结合和隔离促纤维化细胞因子转化生长因子β(转化生长因子β 其N-前肽；5)改变整合素功能。这一提议的中心假设是COL3 指导修复细胞的活动和命运，以最大限度地提高再生反应 皮肤损伤。我们的目标是确定COL3的结构和细胞机制，并 演示含有Col3的生物材料在增强再生反应方面的有效性 伤口愈合。我们建议通过三个主要目标来实现这一目标：确定 胶原蛋白3对胶原蛋白纤维网络的调节特性，共价分子间 瘢痕演变过程中的交联性和粘弹性特性以及角质形成细胞的直接迁移(目的 1)，为了确定COL3在纤维化的肌成纤维细胞分化和持续中的作用， 特别是它对整合素信号和促纤维生长因子可用性的影响(目标2)，以及 证明外源性Col3在受损的小鼠伤口愈合中促进愈合的潜力 目的：在临床前猪模型中限制皮肤损伤后瘢痕的形成(目标3)。 加深我们对Col3如何在皮肤创伤中引导再生反应的理解 修复有可能为其他病理疾病确定新的抗纤维化治疗方法，如肺和 肾纤维化和肝硬变；我们的第三个目标也将使我们能够更多地应用我们的发现 立即转向可翻译的安全干预措施，以治疗虚弱的慢性伤口，并尽量减少 病理性疤痕。因此，我们预计它将对人类健康产生重大影响。