PATHOGENIC MECHANISM OF CONGENITAL ANOMALY AND LIFE-STYLE RELATED DISEASES BASED ON PEROXISOMAL METABOLISM

基于过氧化物酶体代谢的先天性异常及生活方式相关疾病的发病机制

基本信息

批准号：
17591079
负责人：
SHIMOZAWA Nobuyuki
金额：
$ 2.24万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

(1) We have established a diagnostic system of peroxisomal diseases in Japan, and have identified 40 Japanese with peroxisomal biogenesis disorders (PBD), 11 patients with beta-oxidation enzyme deficiencies and more than 100 patients with X-linked adrenoleukodystrophy (ALD).(2) The national history of ALD was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adorescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed.(3) We demonstrated Baicalein 5,6,7-trimethyl ether, a flavonoid derivative may be a candidate for the therapeutic compound for ALD.(4) We investigated the clinical, biochemical and molecular findings, and morphology of peroxisomes in Japanese patients with peroxisomal beta-oxidation enzymes deficiencies, including acyl-CoA oxidase (AOX) or D-3-hydroxyacyl-CoA dehydratase / D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (D-BP).(5) To clarify the molecular mechanism of a temperature-sensitive (TS) phenotype in PBD, we analyzed the protein 3D-structure of a SH3 domein of PEX13 protein, whose Ile326Thr mutation demonstrated a TS phenotype in peroxisomal biogenesis. These data indicated that the Ile326 should be a core residue for folding kinetics and the substitution of the Ile326 by threonine should directly alter the kinetic equilibrium, suggesting a marked increase of the unfolded molecules when the patient had a high fever.

（1）我们在日本建立了一种过氧化物酶体疾病的诊断系统，并确定了40种患有过氧化物酶体生物发生疾病的日本（PBD），11例患有β-氧化酶缺乏症的患者，超过100例X-C-C-C-C-C-C-C-链条adrenelukoukodystrophy（ALD）患者。（2）根据问卷调查的全国回顾性研究，对ALD的国家历史进行了研究。分析了145例患者的数据，包括46例儿童脑形式，39例肾上腺病（AMN），33例，成人脑脑形式，14例，具有前吸收形式和13个具有橄榄球ponto-ponto-cerebellar（OPC）形式的形式。。伴随过氧化物酶体β-氧化酶缺乏，包括酰基-COA氧化酶（AOX）或D-3-羟基乙酰酸-COA脱氢酶 / D-3-羟基乙酰酸-COA脱氢酶脱氢酶双核酶双核酶双蛋白（D-BP）。在PBD中温度敏感的表型（TS）表型中，我们分析了PEX13蛋白的SH3 Domein的蛋白3D结构，其ILE326THR突变在过氧化物酶体生物发生中表现出TS表型。这些数据表明，ILE326应该是折叠动力学的核心残基，苏氨酸替代ILE326应直接改变动力学平衡，表明当患者高发烧时，展开的分子显着增加。