Differential roles of the N-acetylglucosamine N-deacetylase/N-sulfotransferase (NDST) isozymes 1-4 in the development of the mouse

N-乙酰氨基葡萄糖 N-脱乙酰酶/N-磺基转移酶 (NDST) 同工酶 1-4 在小鼠发育中的不同作用

• 批准号: 5153886
• 负责人: Professor Dr. Kay Grobe
• 金额: --
• 依托单位: Institut für Physiologische Chemie und Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 1998
• 资助国家: 德国
• 起止时间: 1997-12-31 至 2002-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5153886?language=en
• 关键词: Differential; roles; acetylglucosamine; deacetylase; sulfotransferase

The objective is the completion of studies on the differential effects of NDST isoenzymes 1-4 in the mouse, with particular emphasis on brain development and immune function, both of which were discovered to depend on NDST function during my previous work. In the past three years, I generated mutant mice defective in NDST-3 (conditional and systemic) which are currently being analyzed. Mice in which NDST-1 was deleted show a condition strongly resembling holoprosencephaly, the most common defect of brain und cranial development in humans associated with SHH (Sonic Hedgehog) signaling. This procet focuses on the critical role of NDST and HS for SHH signaling in the developing mammalian prosencephalon (forebrain). Moreover, a general growth reduction of the prosencephalon can be detected in some offspring (Aprosencephaly), suggesting an additional role of NDST-1 in growth factor (most likely FGF-8) signaling. NDST-1 is also currently being specifically inactivated in T-cells (by crossing conditional NDST knockout mice with mice expressing cre-recombinase under the control of the lck promoter) in order to study the effect on immune function, which needs to be completed.

目的是完成对NDST同工酶1-4在小鼠中的差异效应的研究，特别强调脑发育和免疫功能，这两者在我以前的工作中被发现依赖于NDST功能。在过去的三年里，我产生了NDST-3缺陷突变小鼠（条件性和系统性），目前正在分析。缺失NDST-1的小鼠表现出与前脑无裂畸形非常相似的病症，前脑无裂畸形是人类中与SHH（Sonic Hedgehog）信号传导相关的脑和颅骨发育的最常见缺陷。本论文重点研究了NDST和HS在哺乳动物前脑发育中对SHH信号传导的关键作用。此外，在一些后代（无前脑畸形）中可以检测到前脑的一般生长减少，表明NDST-1在生长因子（最可能是FGF-8）信号传导中的额外作用。NDST-1目前也在T细胞中特异性灭活（通过将条件性NDST敲除小鼠与在lck启动子控制下表达cre重组酶的小鼠杂交），以研究对免疫功能的影响，这需要完成。