PATHOGENESIS OF AMP DEAMINASE DEFICIENCY

AMP脱氨酶及其所属的嘌呤核苷酸循环 成分对许多组织的能量代谢是重要的。 的 该循环在能量代谢中的作用已在 骨骼肌中这些酶的活性 发现了特别高的组织特异性同种型， 随着运动的进行，血液循环的速度急剧增加。 的 强调了骨骼肌中该周期的临床相关性 由遗传性肌病患者发展而来 核苷酸循环酶缺乏。 AMP脱氨酶 缺乏，在这个周期中最常见的缺陷， 患有运动性肌病 这些研究的目的是了解AMP的调节 脱氨酶在正常和病理条件下的表达。 AMP 脱氨酶存在于多种异构体中，其中一些是组织- 特定. 一组项目旨在使用同种型特异性 抗血清和核酸探针来研究发育和 在动物模型中同种型表达的组织特异性控制， 肌细胞分化的组织培养模型。 另一组 实验旨在评估不同领域的功能 的AMP脱氨酶通过使用在体内和体外表达 载体的目标是将异构体特异性特性定位于 不同的领域。 第三组项目旨在 确定遗传性和获得性的分子基础 缺乏AMP脱氨酶通过研究患者使用 同种型特异性和核酸探针。 这些研究的结果与理解 正常人AMP脱氨酶和嘌呤核苷酸循环的控制 条件和了解AMP脱氨酶的发病机制 缺陷 这些结果可能具有更广泛的意义， 对控制肌细胞的过程的进一步了解 分化

AMP deaminase and the purine nucleotide cycle of which it is one component are important for energy metabolism in may tissues. The role of this cycle in energy metabolism has been best studied in skeletal muscle where the activities of these enzymes are particularly high, tissue-specific isoforms are found, and flux through the cycle increases dramatically with exercise. The clinical relevance of this cycle in skeletal muscle is highlighted by the myopathy which develops in patients with inherited deficiencies of nucleotide cycle enzymes. AMP deaminase deficiency, the most common defect in this cycle, is associated with an exercise-related myopathy. The purpose of these studies is to understand the regulation of AMP deaminase expression in normal and pathological conditions. AMP deaminase exists in multiple isoforms, some of which are tissue- specific. One set of projects is designed to use isoform specific anti-sera and nucleic acid probes to study developmental and tissue-specific control of isoform expression in animal models and a tissue culture model of myocyte differentiation. Another set of experiments is designed to assess the function of different domains of AMP deaminase through the use of in vivo and in vitro expression vectors with the goal of localizing isoform-specific properties to different domains. A third set of projects is designed to determine the molecular bases of inherited and acquired deficiencies of AMP deaminase through the study of patients using isoform-specific and nucleic acid probes. Results of these studies have direct relevance to understanding the control of AMP deaminase and the purine nucleotide cycle in normal conditions and to understanding the pathogenesis of AMP deaminase deficiency. The results may have broader significance by providing additional insight to processes which control myocyte differentiation.