Novel Fibronectin-derived Peptides To Support Optimal Fibroblast Adhesion, Migrat

描述(申请人提供)：长期目标：开发和交付新型纤维连接蛋白(FN)衍生的生物活性多肽作为寡肽阵列用于急性伤口和慢性皮肤溃疡，以加速愈合拟议目标：开发新型FN衍生寡肽阵列，支持最佳的成人真皮成纤维细胞黏附和迁移据估计，美国每年有超过3500万例严重皮肤丢失需要主要治疗干预，其中500万例成为慢性溃疡。伤口护理的直接成本为每年97亿美元，占皮肤病年成本的三分之一。尽管我们对伤口病理生物学的了解取得了快速进展，但在急慢性皮肤创伤的护理方面仍难以取得革命性的进展，部分原因是大多数组织工程皮肤替代物含有细胞，这使得质量控制困难，环境条件下的保质期短，用户界面不友好。在这里，我们提出了设计一种商业上可行的无细胞结构的第一步，以再生相对便宜的、生物相容的、诱导生物反应并通过监管(FDA)限制的皮肤。我们实验室以前的研究表明，在猪模型中，三个连接到透明质酸水凝胶上的功能性纤维连接蛋白重组结构域可以促进成人结缔组织细胞的迁移和切除创面的愈合。为了开发商业上可行的组织工程构建，重组结构域必须被小分子寡肽取代：保留结构域的活性；能够以经济有效的方式大规模合成；以及抵抗酶降解。这项建议将重点放在新型的纤维连接蛋白细胞和生长因子结合多肽上，这些多肽将用于黏附三肽RGD的背景下，并测试它们支持细胞黏附、扩散和运动的能力。

DESCRIPTION (provided by applicant): Long-term goal: to develop and deliver novel fibronectin (FN)-derived, bioactive peptides as oligopeptide arrays to acute wounds and chronic skin ulcers to hasten healing Proposed goal: to develop novel FN-derived oligopeptide arrays that support optimal adult human dermal fibroblast adhesion and migration It is estimated that there are greater than 35 million cases of significant skin loss that require major therapeutic intervention in the US per year, 5 million of which become chronic ulcers. Direct cost for wound care is $9.7 billion/year or one-third of all yearly costs for skin disease. Despite rapid progressin our understanding of wound pathobiology, transformative developments in the care of acute and chronic cutaneous wounds have been elusive, partially because most tissue-engineered skin replacements contain cells, which makes quality control difficult, shelf-life under ambient conditions short, and user interface less than friendly. Here we propose the first steps in the design of a commercially viable, acellular construct to regenerate skin that would be relatively inexpensive, biocompatible, induce a biological response and pass regulatory (FDA) constraints. Previous research in our lab demonstrated that three functional fibronectin recombinant domains tethered to a hyaluronan hydrogel enhanced adult human connective tissue cell migration and excisional wound healing in a swine model. To develop a commercially viable tissue-engineered construct, recombinant domains must be replaced by small oligopeptides that: retain activity of domains; can be synthesized on large scale in a cost- effective manner; and resist enzymatic degradation. This proposal will focus on novel fibronectin cell- and growth factor-binding peptides that will be used in the context of the adhesion tri-peptide RGD and tested for their ability to support cell adhesion, spreading and motility.