DISORDERS OF PORPHYRIN METABOLISM

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。迟发性皮肤卟啉病(PCT)是影响人类的最常见的卟啉病形式。PCT的发病率为1-5/25,000名高加索人，其临床特征是皮肤脆弱、大疱性(水疱状)皮损和日光照射下的多毛症(毛发增多)。这种疾病背后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突变杂合子的受试者都没有表现出疾病的体征或症状。这种疾病的表现通常与肝铁超载、接触酒精、丙型肝炎病毒和药用雌激素等肝脏毒素，以及这种疾病的家族史有关。库什纳博士和菲利普斯博士正试图确定这种疾病为什么会表现出来，他们正在检验一种假设，即当肝脏铁负荷过高时，遗传易感人群的肝脏中会产生一种Uro-D抑制物。他们已经开始鉴定从肝活检标本中提取的一种低分子分子，该分子在体外能够抑制重组人Uro-D的活性。从与血色素沉着症基因敲除小鼠杂交的Uro-D基因敲除小鼠的肝脏中分离到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沉着症基因敲除的纯合子)在肝脏中积累了尿卟啉。采用质谱学和串联质谱法确定了尿素酶抑制剂的结构。

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.