Exploring the potential of secondary metabolites derived from marine resources for UV-protection of the human eye/ UVISION 1.1

更广泛的研究背景：菌孢菌素和类菌孢菌素氨基酸（mycosporine-like amino acids，MAAs）是海洋藻类和无脊椎动物的次生代谢产物，在鱼类晶状体中也有大量存在。MAA可防止增强的太阳辐射，因为它们在紫外线范围内表现出非常高的消光系数，具有抵消（紫外线诱导的）自由基形成的能力，并且是光稳定的。尽管努力探索这些独特的化合物的生物医学价值，对哺乳动物抗氧化剂和应激反应途径的干扰知识是有限的。作用模式分析受到MAA可用性和缺乏化学合成方案的阻碍。一个尚未研究的紫外线敏感，脆弱的目标MAA介导的生物活性是人眼。假设：该项目的目标是（I）探索MAA的化学多样性，主要集中在海洋鱼类眼晶状体上，（II）通过使用人类角膜细胞的生物活性指导分级分离支持新MAA的分离和结构分析，（III）升级常见MAA的分离方法，以支持人类细胞中的作用模式分析，（IV）建立MAA的合成路线，（V）MAA对角膜上皮细胞和内皮细胞的二维和三维培养物的活性的探索。将进行靶向生物活性分析，重点关注紫外线防护以外的效应，包括许多细胞保护、炎症和DNA损伤修复机制。在寻找新的行动模式，活动配置文件将最全面地启发应用转录组学为选定MAAs.Methods：从海洋鱼类的眼晶状体将筛选其定性和定量MAA模式。基于FWF前两个项目的方法学经验和发展，项目合作伙伴将沿着细胞和分子生物学方法应用复杂的分离和结构解析技术。此外，还将首次制定甲基丙烯酸化学合成的一般策略。创新：这是一个独特的项目，结合了来自不同领域的科学家的专业知识，旨在扩大对以前未开发的海洋基质中MAA化学多样性的了解，以揭示这些有效的天然紫外线过滤剂在人类角膜细胞上已知靶向途径之外的作用模式，并为它们的化学合成和纯化提供指导。

Wider research context: Mycosporines and mycosporine-like amino acids (both termed as MAAs) are secondary metabolites, which besides marine algae and invertebrates, also occur in remarkable amounts in fish ocular lenses. MAAs protect from enhanced solar radiation, as they exhibit extraordinarily high extinction coefficients in the UV range, have the capacity to counteract (UV-induced) radical formation and are photostable. Despite efforts to explore the biomedical value of these unique compounds, knowledge on interferences with mammalian antioxidant and stress response pathways is limited. Mode of action analysis is hampered by MAA availability and the absence of chemical synthesis protocols. A yet unstudied UV-sensitive, vulnerable target for MAA-mediated bioactivity is the human eye. Hypotheses: Objectives in this project are (I) the exploration of the MAA´s chemical diversity with the main focus on marine fish ocular lenses, (II) the isolation and structural analysis of new MAAs supported by bioactivity-guided fractionation using human corneal cells, (III) the upscaling of isolation methods for common MAAs to support mode of action analysis in human cells, (IV) the establishment of a synthetic route to MAA, and (V) the exploration of MAA activities on 2D and 3D cultures of corneal epithelial and endothelial cells. A targeted bioactivity analysis will be performed focusing on effects beyond UV protection, including a number of cytoprotective, inflammatory and DNA damage repair mechanisms. On the search for novel modes of action, the activity profile will be most comprehensively enlightened applying transcriptomics for selected MAAs.Methods: Ocular lenses from marine fish species will be screened for their qualitative and quantitative MAA patterns. Based on methodological experiences and developments within two previous FWF projects, the project partners will apply sophisticated isolation and structural elucidation techniques along with cell- and molecular biological approaches. In addition, a general strategy for the chemical synthesis of MAAs will be developed for the first time.Innovation: This is a unique project combining the expertise of scientists from different fields that aim to expand the knowledge on the chemical diversity of MAAs in previously unexplored marine matrices, to unravel the mode of action profile of these potent natural UV-filters beyond known target pathways on human corneal cells, and to provide a guideline for their chemical synthesis and purification.