Designing ECM-Inspired Peptide Biomaterials for Regenerative Medicine

项目概述：本研究的长期目标是工程化新的生物材料， 组装肽或肽模拟物以产生可用于组织的合成细胞外基质（ECM 修复或再生。这种方法将使新的治疗牙周伤口愈合，面部软 组织重建以及再生医学和组织工程中的其它应用。作为支架 对于这些疗法，基于肽的生物材料具有先进的性质，例如可调节的生物活性， 高度可控的纤维状结构，以及许多不同肽的复杂呈递， 细胞和材料之间的多种受体特异性相互作用。然而，一个关键问题是， 围绕设计这些支架，使它们具有良好的免疫耐受性，|从逻辑上讲，因为肽 免疫原性可通过多聚化或组装而显著增强。为了解决双重问题， 从天然肽中设计自组装肽生物材料， 在了解肽设计如何影响免疫反应性的同时，该研究被细分为 以下两个目标：目标1）通过以下步骤设计最小修饰的纤维蛋白激发的寡聚化结构域： 理解氨基酸剪裁对折叠和多聚化的影响;目的2）确定 肽剪裁的免疫原性耐受性。这些目标将由一个合作小组完成， 生物医学工程师，结构生物学家和免疫学家，通过设计一系列新颖的多聚体， 受蛋白质纤维蛋白启发的肽，分析肽折叠/寡聚化行为， 二色性光谱和分析超离心，并研究体液和细胞 在小鼠中对所设计的肽的免疫应答。这项研究的成果包括设计 折叠成有用的寡聚化结构的最小免疫原性肽，以及对 肽设计如何影响这些自组装系统中的免疫反应性。因此，本研究将 使未来的研究，从这些设计的肽积木生产的生物材料将是 作为再生医学的新支架。相关性：本研究与公众相关 健康，因为它为重建受损或患病的软组织提供了新的材料。还 研究将拓宽对这类材料如何与免疫系统相互作用的理解。

Project Summary: The long-term goal of this research is to engineer new biomaterials formulated from self- assembling peptides or peptidomimetics to produce synthetic extracellular matrices (ECMs) useful for tissue repair or regeneration. Such approaches will enable new therapies for periodontal wound healing, facial soft tissue reconstruction, and other applications in regenerative medicine and tissue engineering. As scaffolds for these therapies, peptide-based biomaterials possess advanced properties such as tunable bioactivity, highly controllable fibrillar architectures, and complex presentation of many different peptides to provide multiple receptor-specific interactions between cells and the material. A critical issue, however, revolves around designing these scaffolds so that they are well-tolerated immuno|ogically, because peptide immunogenicity can be significantly enhanced by multimerization or assembly. To address the dual issues of designing self-assembling peptide biomaterials from native peptides likely to be tolerated while concurrently understanding how peptide designs impact immunoreactivity, the research is subdivided into the following two aims: Aim 1) Design minimally modified fibrin-inspired oligomerization domains by understanding the impact of amino acid tailoring on folding and multimerization; Aim 2) Determine the immunogenic tolerability of peptide tailoring. These aims will be accomplished by a collaborative team of biomedical engineers, structural biologists, and immunologists by designing a novel series of multimerizing peptides inspired by the protein fibrin, analyzing peptide folding/oligomerization behavior with circular dichroism spectroscopy and analytical ultracentrifugation, and investigating the humoral and cellular immunologic response to the designed peptides in mice. The outcomes of this research include the design of minimally-immunogenic peptides that fold into useful oligomerizing structures and an understanding of how peptide design affects immunoreactivity within these self-assembling systems. Thus, this research will enable future studies in which biomaterials produced from these designed peptide building blocks will be investigated as new scaffolds for regenerative medicine. Relevance: This research is relevant to the public health because it provides new materials for reconstructing damaged or diseased soft tissues. Also, the research will broaden the understanding of how this class of materials interacts with the immune system.