Regulation of extracellular matrix structure as a biological response to chemical stimuli and irradiation

细胞外基质结构的调节作为对化学刺激和辐射的生物反应

基本信息

批准号：
18390041
负责人：
HIGASHI Nobuaki
金额：
$ 10.96万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Heparanase was originally identified as an endo-beta-glucuronidase which cleaves heparan sulfate proteoglycan, and the enzyme' s pathological roles were extensively investigated in the field of cancer biology. In the present study, we examined functional relevance of heparanase in the immune system and biological responses to chemical stimuli and irradiation. Heparanase is involved in degradation of the basement membranes by monocytes. Capping of the molecule on the cell surface and subsequent redistribution at the leading edge are responsible for the degradation. A series of anti-mouse heparanase monoclonal antibodies were established and used to examine the intracellular distribution of the enzyme. Heparanase accumulation in the granules was detected in skin mast cells and in neutrophils in the inflamed microvasculature. Involvement of heparanase in heparin processing and modulation of granular function was examined. When heparanase gene or recombinant proteins were incorporated into MST mastcytoma cells, active heparanase was localized to the granules. In these modified MST cells, granular heparin was cleaved into a smaller molecular size and activity of granular enzymes seemed to be modulated by the low-molecular-weight heparin. Heparanase-mediated cleavage of heparan sulfate and heparin is likely to regulate processes essential to the functions of cells in the immune system and there by greatly involved in biological responses to chemical stimuli and irradiation.

乙酰肝素酶最初被鉴定为一种内切β-葡萄糖醛酸酶，其裂解硫酸乙酰肝素蛋白聚糖，并且该酶的病理作用在癌症生物学领域得到了广泛研究。在本研究中，我们检查了乙酰肝素酶在免疫系统中的功能相关性以及对化学刺激和辐射的生物反应。乙酰肝素酶参与单核细胞的基底膜降解。细胞表面上的分子加帽以及随后在前缘的重新分布是降解的原因。建立了一系列抗小鼠乙酰肝素酶单克隆抗体并用于检查该酶的细胞内分布。在皮肤肥大细胞和发炎的微血管系统的中性粒细胞中检测到颗粒中乙酰肝素酶的积累。检查了乙酰肝素酶参与肝素加工和颗粒功能调节的情况。当乙酰肝素酶基因或重组蛋白被整合到MST肥大细胞瘤细胞中时，活性乙酰肝素酶定位于颗粒。在这些改良的 MST 细胞中，颗粒肝素被切割成较小的分子尺寸，颗粒酶的活性似乎受到低分子量肝素的调节。乙酰肝素酶介导的硫酸乙酰肝素和肝素的裂解可能调节免疫系统中细胞功能所必需的过程，从而极大地参与对化学刺激和辐射的生物反应。