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: 9788486
• 负责人: SUSAN W VOLK
• 金额: $ 38.78万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788486
• 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; Cutaneous; Cysteine; Data; Deposition; Dermal; Dermis; Development; Disease; Environment; Epithelial Cells; Equilibrium; Evolution; Extracellular Matrix; Extracellular Matrix Proteins; Family suidae; Fetus; Fibrillar Collagen; Fibroblasts; Future; Goals; Granulation Tissue; Growth Factor; Health; Health Care Costs; Health Expenditures; Human; Impaired wound healing; Impairment; In Vitro; Inferior; Injury; Integrins; Intervention; Lead; Liver Cirrhosis; Mechanics; Mediating; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Natural regeneration; Normal tissue morphology; Outcome; Pathologic; Pathology; Play; Process; Property; Publishing; Pulmonary Fibrosis; Regenerative response; Regulation; Resistance; Role; Science; Signal Transduction; Skin; Skin wound; Structure; Testing; Therapeutic; Tissues; Transforming Growth Factors; United States; Wound Healing; 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; pre-clinical; prevent; psychosocial; regenerative; repaired; response; response to injury; restoration; spatiotemporal; viscoelasticity; wound

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.

异常伤口愈合反应，包括慢性不愈合伤口和过度愈合伤口。 在美国，皮肤瘢痕形成导致显著的发病率和医疗保健支出， 国际吧细胞外基质（ECM）通过调节细胞增殖、分化、增殖和凋亡，在创伤修复中起着重要作用。 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（Col 3）是ECM的一种成分，被认为在创伤修复中起重要作用 由于其在该过程的早期表达增加，其确切作用仍然是个谜。我们的研究 表明Col 3在伤口愈合中具有关键作用，不同于I型胶原（Col 1）。具体地说， 我们在体外和体内发表的和初步的数据提供了证据，Col 3调节修复性 细胞活动和命运通过1）改变ECM组织和结构以直接机械通信 2）促进角质形成细胞迁移以改善上皮再生;和3） 通过抑制肌成纤维细胞的分化和持久性来限制瘢痕形成， 伤口的细胞。额外的初步数据支持Col 3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（TGFβ）， 其N-前肽，和5）改变整联蛋白功能。这个提议的核心假设是，Col 3 指导修复细胞的活动和命运，使再生反应最大化， 皮肤损伤我们的目标是确定Col 3的结构和细胞机制， 证明了含Col 3的生物材料在治疗过程中增强再生反应的功效。 伤口愈合我们建议通过三个主要目标来实现这一目标： 胶原纤维网络上的Col 3调节胶原纤维特性，共价分子间 交联和粘弹性，并指导角质形成细胞迁移（目的 1），确定Col 3在纤维化肌成纤维细胞的分化和持久性中的作用， 特别是其对整合素信号传导和促纤维化生长因子可用性的影响（Aim 2），以及 证明外源性Col 3在受损的鼠伤口愈合中恢复愈合的潜力 在临床前的猪模型中，在皮肤损伤后限制瘢痕形成（目的3）。 提高我们对Col 3在皮肤创伤期间如何指导再生反应的理解 修复有可能为其他病理学如肺和肺纤维化确定新的抗纤维化疗法。 肾纤维化和肝硬化;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 立即转化为可转化和安全的干预措施，以治疗使人衰弱的慢性伤口， 病理性疤痕因此，我们预计它将对人类健康产生重大影响。