ERI: Controlling Non-Specific Peptide Degradation in Hydrogels

开发模拟人体组织的生物材料系统对于提高我们对生物学的理解和治疗疾病的能力至关重要。这些材料通常被肽功能化，肽是一种短的蛋白质片段，因此支架可以更好地模拟体内的环境。然而，细胞可以降解这些肽，并且需要更好地了解肽化学如何影响降解速率，以及这如何改变细胞与这些支架的相互作用。这个ERI项目将首先设计一系列具有不同化学功能的肽，以了解改变端基化学如何促进肽的稳定性，然后表明减少降解会改变细胞在水凝胶内的附着和迁移方式。该提案的研究计划将与当地博物馆合作，为当地中学生开发模块，让他们使用各种制造技术“制作”自己的生物材料。这些简短的模块将展示工业革命期间使用的技术，如铸造和挤压，今天仍然用于制造生物材料。生物工程系统将在提高我们对人体生理学的理解和发展未来的再生疗法方面发挥关键作用。其中许多使用具有生物活性基团功能化的聚合物或聚合物网络的生物材料，用于各种目的，包括细胞粘附和信号传导。多肽通常用于这种能力，因为它们与细胞自然结合，化学稳定，并且可以很容易地纳入大多数生物材料系统。然而，许多这些肽抗酶降解的稳定性还没有被量化。这项工作的中心假设是，生物材料支架中存在非特异性细胞分泌蛋白酶降解，这会降低生物活性，这可以通过在末端使用非天然氨基酸来防止。该项目将使用肽库来实现两个特定目标：(1)量化具有不同末端功能化的库肽的非特异性降解；(2)确定细胞粘附、扩散和迁移的程度取决于细胞粘附肽RGD（精氨酸-甘氨酸-天冬氨酸）的酶稳定性。这些信息将有助于其他实验室为生物工程系统设计具有更高稳定性的肽，这将提高肽修饰生物材料的功效。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Developing biomaterial systems that mimic human tissues are vital for improving our understanding of biology and our ability to treat diseases. These materials are often functionalized with peptides, which are short protein fragments, so that the scaffolds better mimic the environment found inside the body. However, cells can degrade these peptides, and a better understanding of how peptide chemistry influences the degradation rate, and how this then changes how cells interact with these scaffolds is needed. This ERI project will first design a series of peptides with different chemical functionalities to understand how changing the end group chemistry can promote peptide stability, and then show that reducing degradation changes how cells attach and migrate within hydrogels. The research plan of this proposal will be paired with outreach efforts in collaboration with a local museum to develop modules for local middle school students to “make” their own biomaterials using a variety of fabrication techniques. These short modules will show how technologies used during the industrial revolution, such as casting and extrusion, are still used today to make biomaterials.Bioengineered systems will play a crucial role in improving our understanding of human physiology and developing future regenerative therapies. Many of these use biomaterials featuring a polymer or polymer network that is functionalized with bioactive groups for a variety of purposes, including cell adhesion and signaling. Peptides are commonly used in this capacity as they naturally interface with cells, are chemically stable, and can easily be incorporated into most biomaterial systems. However, the stability of many of these peptides against enzymatic degradation has not been quantified. The central hypothesis of this work is that non-specific cell-secreted protease degradation is present in biomaterial scaffolds, which decreases biological activity, and this can be prevented using nonnatural amino acids at the termini. The project will use a library of peptides to achieve two specific objectives: (1) Quantify the non-specific degradation of a library peptides with different terminal functionalizations and (2) Determine the extent to which cell adhesion, spreading, and migration depends upon the enzymatic stability of the cell adhesion peptide RGD (arginine-glycine-aspartate). This information will help other labs design peptides for bioengineering systems with increased stability which will improve the efficacy of peptide-modified biomaterials.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.