LYMPHOBLAST MODEL FOR DISEASES OF PURINE METABOLISM

描述：赫什菲尔德博士实验室的长期目标是 一直在定义遗传缺陷的致病生化影响 腺苷脱氨酶(ADA)是导致 其临床后果，以期开发有缺陷的治疗方法。这个 ADA缺乏的主要后果是混合性免疫缺陷， 通常以严重的形式(SCID)发生在婴儿中，但也可能发展为 潜伏在年龄较大的儿童、青少年或成人中。实验室的 过去对免疫缺陷的发病机制的研究一直是 对于开发一种有效形式的酶替代很重要 治疗(聚乙二醇腺苷)。该实验室参与监测治疗情况。 接受PEG-ADA治疗的患者，因此他们将最近的 鉴定导致ADA缺乏的突变的研究。 本提案将继续这些努力，以便更好地界定 特异性突变与酶缺乏程度的关系 代谢和临床严重性，对酶(和基因)的反应 替代疗法。为了推进这一目标，调查人员 建议系统地研究突变对 利用一株缺乏ADA活性的大肠杆菌表达ADA活性 细菌ADA基因。他们还将研究伴侣的作用。 蛋白质对突变的ADA表达的影响，以确定 对蛋白质折叠造成潜在的可逆影响。这是最近发生的 得知ADA缺陷(“基因敲除”)小鼠死于肝细胞 ADA缺乏也会导致人类肝炎 病人。他们将研究基因敲除小鼠作为模型系统 进行不能在人类病人身上进行的生化研究。

DESCRIPTION: The long-term objectives of Dr. Hershfield's laboratory have been to define the pathogenic biochemical effects of inherited deficiency of the enzyme adenosine deaminase (ADA) that are responsible for causing its clinical consequences, in order to develop defective therapy. The primary consequence of ADA deficiency is Combined Immune Deficiency, which usually occurs in a "severe" form (SCID) in infants, but may also develop insidiously in older children, adolescents, or adults. The laboratory's past research on the pathogenesis of the immune deficiency has been important to the development of an effective form of enzyme replacement therapy (PEG-ADA). The laboratory is involved in monitoring treatment of patients receiving PEG-ADA, and as a result they have focused their recent research on identifying mutations responsible for causing ADA deficiency. The present proposal will continue these efforts to better define the relationship of specific mutations to the degree of enzyme deficiency metabolic and clinical severity, in response to enzyme (and gene) replacement therapy. To further this objective the investigators have proposed to systematically investigate the effects of mutations on the expression of ADA activity, using a strain of E. coli that lacks the bacterial ADA gene. They will also investigate the effects of chaperonin proteins on mutant ADA expression in order to identify mutations that cause potentially reversible effects on protein folding. It recently been learned that ADA deficient ("knockout") mice die from liver cell degeneration, and that ADA deficiency can also cause hepatitis in human patients. They will investigate the knockout mice as a model system to carry out biochemical studies that could not be done in human patients.