ERYTHROPOIETIC PROTOPORPHYRIA: MECHANISMS OF DISEASE

描述（改编自申请人摘要）：人原卟啉症 是血红素生物合成中的遗传决定的代谢缺陷。 部分 骨髓中铁螯合酶（FC）活性缺乏 红系细胞导致原卟啉（PP）在RBC中积累， 血浆肝脏和粪便 PP引起疼痛的皮肤光敏性， 可能导致受影响儿童和成人的致命性肝毒性。 多 关于人类原卟啉症的自然过程仍然未知， 其发病机制在皮肤、骨髓和肝脏中。 继续 正在进行的一项已确立的原卟啉症研究的纵向调查 使用已建立数据库的标准化协议进行人口普查 在目前参与的24个国家中， 患者，将进一步推进目前对这种疾病如何 在大量仔细研究的个体患者中发展， 很多年的时间 个别患者可能受益于早期发现 肝功能的不良变化。 导致发展的因素 致死性肝毒性可以从回顾性分析 积累的数据库，用于发生肝功能障碍的患者， 与整个人口的数据相比。 阐明 人FC结构和功能将通过生物化学和 免疫学方法。 通过新方法生产的纯化的FC蛋白 研究人员已经开发出的色谱方法将 用于生产多克隆和单克隆抗体， 本文提出的突变体与正常人FC的表征研究。 这种免疫试剂和寡核苷酸探针的开发 根据来源于以下的氨基酸序列信息构建： 从纯化的人FC裂解的肽将使它们，在未来的几年， 提出克隆和表达人类FC的基因， 其染色体分配，并确定其确切的性质， 导致人类原卟啉症的FC突变。 FC的体内稳定性 将首先在药物诱导的大鼠红细胞生成中评价 和骨髓生成模型，然后在人原卟啉骨髓中。 临床和实验室评价几个相关的不寻常的情况下， 已经提供了新的信息， 这组疾病将继续下去。 特别是， 卟啉病表皮-真皮分离的显微解剖学水平 将进行迟发性皮肤移植以靶向适当的生物分子 基底膜区的成分进行进一步研究。

DESCRIPTION (Adapted from the applicant's abstract): Human protoporphyria is a genetically determined metabolic defect in heme biosynthesis. Partial deficiency in the activity of the enzyme ferrochelatase (FC) in bone marrow erythroid cells results in accumulation of protoporphyrin (PP) in rbc, plasma, liver, and feces. PP causes painful cutaneous photosensitivity and may lead to fatal hepatotoxicity in affected children and adults. Much remains unknown about the natural course of human protoporphyria and about its disease mechanisms in skin, bone marrow, and liver. Continuation of ongoing longitudinal investigations of an established protoporphyria study population with a standardized protocol that has already built a data base for 8 years or longer in the majority of 24 currently participating patients, will further advance current understanding of how this disease evolves in a large number of carefully studied individual patients over many years of time. Individual patients may benefit from early detection of adverse changes in hepatic function. Factors leading to development of fatal hepatotoxicity may be learned from retrospective analysis of the accumulated data base for patients who develop liver dysfunction when compared with the data of the population as a whole. Elucidation of the structure and function of human FC will be advanced by biochemical and immunological methods. Purified FC protein produced by novel chromatographic methods that the investigators have already developed will be used to produce polyclonal and monoclonal antibodies useful for characterization studies of mutant versus normal human FCs proposed herein. Development of such immunological reagents and of oligonucleotide probes constructed according to amino acid sequence information derived from peptides cleaved from purified human FC will enable them, in future years, to propose to clone and express the gene for human FC, to initiate a search for its chromosomal assignment, and to determine the precise nature of the FC mutation responsible for human protoporphyria. In vivo stability of FC in bone marrow will be evaluated first in drug-induced rat erythropoiesis and myelopoiesis models, then in human protoporphyric bone marrow. Clinical and laboratory evaluations of unusual cases of several related forms of porphyria that have already provided new information regarding this group of diseases will be continued. In particular, immunomapping of the microanatomical level of the epidermal-dermal separation in porphyria cutanea tarda will be carried out to target appropriate biomolecular components of the basement membrane zone for further study.