N-Glycosylation and Ocular Surface Homeostasis

N-糖基化和眼表稳态

• 批准号: 10578975
• 负责人: Pablo Argueso
• 金额: $ 36.38万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578975
• 关键词: Glycosylation; Ocular; Surface; Homeostasis

Project Summary/Abstract All cells in nature are coated with a diverse mixture of glycans called the glycocalyx that functions as the primary interface with the environment. The structure of the glycocalyx is controlled by a series of glycosyltransferases, glycosidases and glycan-modifying enzymes that collectively assemble and process monosaccharide moieties to generate cell surface signatures in a tissue-specific manner. Recent findings indicate cell surface glycans perform important roles in stem cells and have a critical impact during both developmental processes and maintenance of homeostasis in the adult. This proposal centers on a major gap in our understanding of how cell surface glycans contribute to maintain limbal epithelial stem cell homeostasis. The proliferative capacity of the stem cells in tissues with high cellular turnover has to be precisely regulated to maintain regenerative capacity while preventing abnormal growth. It has become increasingly clear that modification of cell surface receptors by core fucosylation is critical to promote specific signal tranduction pathways and to regulate biological functions relevant to cell proliferation and differentiation. We hypothesize that lack of core fucosylation plays an important role in modulating the proliferative capacity of limbal epithelial stem cells and in promoting their self-renewal properties. The following specific aims will address this objective: (1) to identify glycan signatures in limbal epithelial stem cells and how they change during differentiation, (2) to investigate the contribution of FUT8, the only fucosyltransferase that catalyzes the addition of core fucose to N-glycans, in regulating growth factor receptor signaling and cellular turnover in limbal epithelial cells, and (3) to investigate whether core fucosylation can be used as a novel method to isolate and transplant limbal epithelial stem cells with high self-renewal and proliferative capacities. It is anticipated that this research will have significant translational relevance given the emerging focus on cell replacement therapies for limbal stem cell deficiency.

项目总结/摘要 自然界中的所有细胞都被称为糖萼的各种聚糖混合物所覆盖， 与环境的主要接口。糖萼的结构是由一系列的 糖基转移酶、糖苷酶和聚糖修饰酶共同组装和加工 在一些实施方案中，所述方法包括使用单糖部分以组织特异性方式产生细胞表面特征。最近的调查结果 表明细胞表面聚糖在干细胞中起重要作用， 发育过程和维持体内平衡。 这项建议集中在我们对细胞表面聚糖如何有助于细胞增殖的理解中的一个主要空白。 维持角膜缘上皮干细胞稳态。高分化组织中干细胞的增殖能力 细胞周转必须精确调节，以保持再生能力，同时防止异常 增长越来越清楚的是，通过核心岩藻糖基化修饰细胞表面受体是一种有效的方法。 对促进特定的信号转导通路和调节与细胞相关的生物学功能至关重要 增殖和分化。我们假设核心岩藻糖基化的缺乏在 调节角膜缘上皮干细胞的增殖能力并促进其自我更新 特性. 以下具体目标将解决这一目标：（1）识别角膜缘上皮细胞中的聚糖标签 干细胞以及它们在分化过程中如何变化，（2）研究FUT 8的贡献，FUT 8是唯一的 在调节生长因子受体中催化核心岩藻糖添加到N-聚糖的岩藻糖基转移酶 （3）研究核心岩藻糖基化是否可以在角膜缘上皮细胞中表达， 作为一种分离和移植具有高度自我更新能力的角膜缘上皮干细胞的新方法， 增殖能力预计这项研究将具有重大的翻译相关性， 角膜缘干细胞缺乏的细胞替代疗法的新焦点。