Designing ECM-Inspired Peptide Biomaterials for Regenerative Medicine

项目概述：本研究的长期目标是设计由自组装肽或拟肽制剂配制的新生物材料，以生产用于组织修复或再生的合成细胞外基质（ecm）。这些方法将为牙周伤口愈合、面部软组织重建以及再生医学和组织工程中的其他应用提供新的治疗方法。作为这些疗法的支架，基于肽的生物材料具有先进的特性，如可调节的生物活性，高度可控的纤维结构，以及许多不同肽的复杂呈现，以提供细胞和材料之间的多种受体特异性相互作用。然而，一个关键的问题是如何设计这些支架，使其具有良好的免疫耐受能力，因为多肽的免疫原性可以通过多聚或组装得到显著增强。为了解决从可能耐受的天然肽设计自组装肽生物材料的双重问题，同时了解肽设计如何影响免疫反应性，该研究分为以下两个目标：目标1)通过了解氨基酸剪裁对折叠和多聚化的影响，设计最小修饰的纤维蛋白激发的寡聚化结构域；目的2)确定肽裁剪的免疫原耐受性。这些目标将由一个由生物医学工程师、结构生物学家和免疫学家组成的合作团队完成，他们将设计一系列受纤维蛋白启发的多聚肽，利用圆二色光谱和分析超离心分析肽的折叠/寡聚行为，并研究小鼠对所设计肽的体液和细胞免疫反应。这项研究的结果包括设计最小免疫原性肽，折叠成有用的寡聚结构，并了解肽设计如何影响这些自组装系统中的免疫反应性。因此，这项研究将使未来的研究成为可能，从这些设计的肽构建块中产生的生物材料将被研究为再生医学的新支架。相关性：本研究为重建受损或病变的软组织提供了新的材料，与公众健康相关。此外，这项研究将扩大对这类材料如何与免疫系统相互作用的理解。

DESCRIPTION (provided by applicant): 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.