Role of the chito-structural code in controlling inflammatory and tissue regenerative processes in the frame of biomedical applications

甲壳素是地球上含量最丰富的生物聚合物之一，是节肢动物外壳、头足类内骨骼和真菌细胞壁的一部分。它是由N-乙酰氨基葡萄糖残基组成的不溶于水的分子。它的部分脱乙酰化过程，例如在人类致病真菌中发现的过程，促进了共聚物在水介质中的溶解，一旦它溶解，就被称为壳聚糖。最近的研究表明，剩余的乙酰基的数量和模式对应于一个生化密码，这是与生物环境相互作用的关键。这项拟议的研究的目的是更好地了解这种甲壳素编码(编码χ)与哺乳动物的生物反应之间的结构-功能关系。在前期研究的基础上，我们打算分析几丁质/壳聚糖与补体系统、几丁质结合蛋白YKL-40和硫酸乙酰肝素蛋白多糖之间的分子串扰。补体系统是体液天然免疫系统中古老的一部分，我们最近发现它们是壳聚糖的结合伙伴。甲壳素被证明能诱导细胞的先天免疫反应，如巨噬细胞的激活。相比之下，壳聚糖被认为是一种很有前途的生物材料，可以促进伤口愈合和组织再生。为了了解控制甲壳素和壳聚糖广泛生物学性质的潜在密码χ，我们将在分子水平上进行相互作用研究，与哺乳动物细胞进行体外实验，并使用小鼠模型进行体内测量。我们研究项目的基础是CHIT-聚合物物理水凝胶，它特别适合于体外实验和小鼠局部、微创的体内应用，以研究免疫细胞招募等炎症事件或血管生成等再生过程。

Chitin, one of the most abundant biopolymers on Earth, is part of arthropod shells, cephalopod endoskeleton, and fungal cell walls. It is a water insoluble molecule composed of N-acetyl glucosamine residues. Its partial de-acetylation, a process found e.g. in human pathogenic fungi promotes the solubility of the copolymer in aqueous media, which is called chitosan once it is soluble. Recent studies indicate that the amount and the pattern of the remaining acetyl groups, corresponds to a biochemical code, which is critical for the interaction with the biological environment. The aim of the proposed research is to better understand the structure-functional relationship between this chitin code (codeχ) and the biological response in mammalians. Based on our previous and preliminary studies, we intend to analyze the molecular crosstalk of chitin/chitosan with the complement system, an ancient part of the humoral innate immune system, the chitin-binding protein YKL-40 and heparan sulfate proteoglycans, which we have recently identified as binding partners of chitosans. Chitin was shown to induce the cellular innate immune response such as the activation of macrophages. In contrast, chitosan is postulated as promising biomaterial, which promotes wound healing and tissue regeneration. To understand the underlying codeχ controlling the broad range of biological properties of chitin and chitosan, we will perform interaction studies on the molecular level, in vitro experiments with mammalian cells and in vivo measurements using mouse models. The basis for our research project are chit-polymer physical hydrogels, which are particularly suitable for in vitro experiments and a localized, minimally invasive in vivo application in mice to investigate inflammatory events such as immune cell recruitment or regenerative processes such as angiogenesis.