ERYTHROPOIETIC PROTOPORPHYRIA--MECHANISMS OF DISEASE

描述(改编自申请者的摘要)：人类原卟啉 是一种由基因决定的血红素生物合成代谢缺陷。部分 骨髓中铁螯合酶(Fc)活性缺陷 红系细胞导致原卟啉(PP)在红细胞中积聚， 血浆、肝脏和粪便。PP会导致疼痛的皮肤光敏和 可能会对受影响的儿童和成人造成致命的肝毒性。大有可为 关于人类原卟啉症的自然过程和大约 其在皮肤、骨髓和肝脏中的发病机制。延续 正在进行的一项已建立的原卟啉研究的纵向调查 使用已建立数据库的标准化协议进行填充 在目前参与的24人中，大多数人的任期为8年或更长时间 患者，将进一步促进目前对这种疾病如何 在经过仔细研究的大量个体患者中进化而来 很多年的时间了。个别患者可能从早期发现中受益 肝功能的不良变化。导致……发展的因素 致命的肝毒性可以从对 出现肝功能障碍的患者的累积数据库 与整个人口的数据进行比较。澄清： 生物化学和生物化学将促进人类Fc的结构和功能 免疫学方法。新型菌株生产纯化Fc蛋白的研究 研究人员已经开发出的层析方法将 用于生产多克隆和单抗，可用于 本文提出了突变人FCS与正常人FCS的特征研究。 此类免疫试剂及寡核苷酸探针的研究进展 根据源自于 从纯化的人Fc中分离出的多肽将使它们在未来几年里， 建议克隆和表达人Fc基因，以启动搜索 为它的染色体分配，并确定准确的性质 人类原卟啉症的致病基因Fc突变。FC的体内稳定性研究 将首先在药物诱导的大鼠红细胞生成中进行评估 以及骨髓生成模型，然后在人类原始骨盆骨髓中。 几种相关异常病例的临床和实验室评价 已经提供了关于以下方面的新信息的卟啉类型 这组疾病将继续存在。特别是，免疫标记法 卟啉症表皮-真皮分离的显微解剖水平 迟发性皮肤损伤将以适当的生物分子为靶点 基底膜带的成分有待进一步研究。

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.