DISORDERS OF PORPHYRIN METABOLISM

卟啉代谢紊乱

• 批准号: 7376456
• 负责人: JAMES P KUSHNER
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376456
• 关键词: emotions; gene mutation; genes; genetically modified animals; human; iron poisoning; laboratory mouse; liver; mass spectrometry

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Porphyria cutanea tarda (PCT) is the most common form of porphyria affecting humans. PCT occurs with the prevalence of 1 to 5/25,000 Caucasians and is clinically characterized by skin fragility, bullous (blister-like) lesions and hypertrichosis (increased hair growth) on sun-exposed areas. The genetic defects underlying this disorder are mutations affecting the uroporphyrinogen decarboxylase (URO-D) gene but most subjects heterozygous for URO-D mutations do not express signs or symptoms of the disease. Expression of the disorder generally is associated with liver iron overload, exposure to liver toxins such as alcohol, the hepatitis C virus and medicinal estrogens, and a familial history of the disorder. Drs. Kushner and Philllips are attempting to determine why the disease is expressed and they are testing the hypothesis that an inhibitor of URO-D is generated in the liver of individuals genetically predisposed to develop PCT when liver iron overload occurs. They have begun to characterize a low molecular weight molecule extracted from liver biopsy specimens that has the ability to inhibit the activity of recombinant human URO-D in vitro. A compound with identical physical properties has been isolated from the livers of URO-D knockout mice that have been crossbred with hemochromatosis gene knockout mice. The result is that these animals (heterozygous for the URO-D knockout and homozygous for the hemochromatosis gene knockout) accumulate uroporphyrin in the liver. Mass spectrometry and tandem mass spectrometry are being employed to establish the structure of the URO-Dinhibitor.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。迟发性皮肤卟啉症 (PCT) 是影响人类的最常见的卟啉症。 PCT 在白种人中的患病率为 1 至 5/25,000，其临床特征为皮肤脆弱、大疱（水疱样）病变和暴露于阳光区域的多毛症（毛发生长增加）。这种疾病的遗传缺陷是影响尿卟啉原脱羧酶 (URO-D) 基因的突变，但大多数 URO-D 突变杂合受试者并不表现出该疾病的体征或症状。该疾病的表现通常与肝铁超载、接触肝脏毒素（例如酒精、丙型肝炎病毒和药用雌激素）以及该疾病的家族史有关。博士。库什纳和菲利普斯正试图确定这种疾病为何会出现，并且他们正在测试这样的假设：当肝脏铁超载发生时，在遗传上易患 PCT 的个体的肝脏中会产生 URO-D 抑制剂。他们已经开始鉴定从肝活检标本中提取的一种低分子量分子，该分子能够在体外抑制重组人 URO-D 的活性。从与血色素沉着病基因敲除小鼠杂交的 URO-D 敲除小鼠的肝脏中分离出一种具有相同物理性质的化合物。结果是这些动物（URO-D 基因敲除的杂合子和血色素沉着病基因敲除的纯合子）在肝脏中积聚尿卟啉。质谱法和串联质谱法被用来建立 URO-抑制剂的结构。