Fibronectin peptides for treatment of burns

纤连蛋白肽治疗烧伤

• 批准号: 7326655
• 负责人: RICHARD August CLARK
• 金额: $ 10万
• 依托单位: NEOMATRIX FORMULATIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326655
• 关键词: Accident and Emergency department; Address; Admission activity; Amino Acids; Binding; Biological Assay; Burn injury; Cell Survival; Cells; Cessation of life; Cicatrix; Collagen; Cultured Cells; Cutaneous; Depth; Development; Endothelial Cells; Engineering; Environment; Family suidae; Fibroblasts; Fibronectins; Growth Factor; Healed; Hospitals; Hyaluronan; In Vitro; Injury; Investigation; Laboratories; Methods; Modeling; Movement; Patient Care; Peptides; Platelet-Derived Growth Factor; Principal Investigator; Research; Sepsis; Site; Speed; Supporting Cell; Testing; Thick; Tissues; Topical Preparation; Visit; Wound Healing; burn therapy; cell motility; crosslink; day; healing; human migration; in vitro Model; in vivo; migration; mortality; novel; platelet-derived growth factor BB; prevent; programs; tissue culture; wound

DESCRIPTION (provided by applicant): There are more than 1 million burns each year in the US, resulting in 700,000 emergency department visits, 45,000 hospital admissions, and 4,500 deaths. Burns are dynamic injuries characterized by progressive extension of the injury over the first few days. Progression of partial thickness burns to full thickness injuries is associated with increases in mortality, wound sepsis, and scar formation. Methods aimed at preventing burn progression have been the focus of intense research but these results have been disappointing. In fact the unmet challenge of burn treatment is development of a therapy that limits injury, speeds healing and reduces scarring. Discovery of novel methods to successfully address this challenge would be a major advance in the care of patients with burns. Over the past decade the Clark laboratory has made several critical observations about new tissue formation in wounds. These in vivo investigations stimulated the development of a novel in vitro model of cell migration across matrix boundaries as would be found in early healing wounds. The assay has also been utilized to screen new matrix materials for their ability to support cell migration from a collagen matrix, as would be found in a periwound environment, into a neomatrix. Subsequently, 3 fibronectin (FN) functional domains were found to be necessary and sufficient for fibroblast movement. From this discovery, an intermolecular cross-linked hyaluronan (HA) decorated with the 3 FN domains was engineered and demonstrated to enhance fibroblast migration in vitro and in porcine cutaneous wound repair in vivo. Recently, 4 sites in 3 FN domains were found to bind platelet-derived growth factor-BB (PDGF-BB). PDGF-BB remained active while bound to these FN growth factor (GF)-binding domains or peptides. Importantly the ability of PDGF-BB to act as a survival factor for FN-deficient cells is dependent on FN GF-binding domains or peptides. Since burn wounds can be deficient in FN through thermal denaturation and enzymatic degradation, these findings raise the possibility that FN GF-binding domains or peptides may be useful in burn therapy. Here we propose to create a topical preparation for deep partial thickness burn wounds containing a FN growth factor-enhancing peptide (GFEP). To this end we propose to screen small (<15 amino acid) FN peptides for their ability to bind PDGF-BB and promote FN null fibroblast survival and proliferation (AIM 1), assay FN PDGF-binding peptides in conjunction with PDGF for their ability to promote activation, proliferation and migration of human fibroblasts and microvascular endothelial cells (AIM 2), and test FN PDGF-binding peptides in conjunction with PDGF for their capacity to limit injury, enhance healing and prevent scarring of burn wounds in a porcine model that has been previously validated (AIM 3). There are more than 1 million burns each year in the US, resulting in 700,000 emergency department visits, 45,000 hospital admissions, and 4,500 deaths. Methods aimed at preventing burn progression have been the focus of intense research but these results have been disappointing. Here we propose to create a topical preparation for deep partial thickness burn wounds containing a growth factor-enhancing peptide that was recently discovered at SUNY Stony Brook and has the remarkable ability to promote tissue cultured cell survival and proliferation.

描述（由申请人提供）：美国每年有超过 100 万起烧伤，导致 700,000 人次急诊就诊，45,000 人入院治疗，以及 4,500 人死亡。烧伤是动态损伤，其特征是在最初几天内损伤逐渐扩大。部分层烧伤进展为全层损伤与死亡率、伤口败血症和疤痕形成的增加有关。旨在预防烧伤进展的方法一直是深入研究的焦点，但这些结果令人失望。事实上，烧伤治疗尚未解决的挑战是开发一种限制损伤、加速愈合和减少疤痕的疗法。发现成功应对这一挑战的新方法将是烧伤患者护理方面的重大进步。在过去的十年中，克拉克实验室对伤口中新组织的形成进行了多项重要观察。这些体内研究刺激了细胞跨基质边界迁移的新型体外模型的发展，就像在早期愈合伤口中发现的那样。该测定还用于筛选新的基质材料，以确定它们是否能够支持细胞从胶原基质（如在伤口周围环境中发现的）迁移到新基质中。随后，发现 3 个纤连蛋白 (FN) 功能域对于成纤维细胞运动是必要且充分的。根据这一发现，我们设计了一种装饰有 3 个 FN 结构域的分子间交联透明质酸 (HA)，并证明其能够增强体外成纤维细胞迁移和体内猪皮肤伤口修复。最近，发现 3 个 FN 结构域中的 4 个位点可结合血小板衍生生长因子-BB (PDGF-BB)。 PDGF-BB 在与这些 FN 生长因子 (GF) 结合结构域或肽结合时保持活性。重要的是，PDGF-BB 作为 FN 缺陷细胞的生存因子的能力取决于 FN GF 结合结构域或肽。由于烧伤创面可能因热变性和酶降解而缺乏 FN，因此这些发现提出了 FN GF 结合结构域或肽可用于烧伤治疗的可能性。在这里，我们建议为深部烧伤创面制作一种含有 FN 生长因子增强肽 (GFEP) 的局部制剂。为此，我们建议筛选小（<15个氨基酸）FN肽结合PDGF-BB并促进FN无效成纤维细胞存活和增殖的能力（AIM 1），测定FN PDGF结合肽与PDGF结合促进人成纤维细胞和微血管内皮细胞活化、增殖和迁移的能力（AIM 2），并测试 FN PDGF 结合肽与 PDGF 结合使用，可在猪模型中限制损伤、促进愈合并防止烧伤疤痕形成（AIM 3）。美国每年有超过 100 万起烧伤，导致 70 万人次急诊就诊、45,000 人入院治疗以及 4,500 人死亡。旨在预防烧伤进展的方法一直是深入研究的焦点，但这些结果令人失望。在这里，我们建议为深部烧伤创面制作一种局部制剂，其中含有一种生长因子增强肽，这种肽是最近在纽约州立大学石溪分校发现的，具有促进组织培养细胞存活和增殖的显着能力。