Preclinical Studies of Ataxia-Telangiectasia

超出所提供的空间。该项目旨在改善共济失调毛细血管扩张症（A-T）患者的诊断和治疗，这是一种进行性和致命的儿童神经系统疾病。正在建立一个充分表征的A-T患者资源，用于未来的临床试验。受影响的单倍型及其携带的ATM突变将在400多个不同种族人群的家庭中被鉴定出来，希望基于这些信息，可以很快设计出自动化的突变检测方法。将定义约50个西班牙裔美国人家族的单倍型、突变和表型，并与来自墨西哥、中美洲和南美洲以及西班牙的约150个其他西班牙裔背景的A-T家族进行比较。受影响的基因型和表型之间的潜在相关性将进行调查，以确定ATM蛋白的新功能域，并提高我们预测疾病进展的能力。利用新建立的重组牛痘病毒表达系统，ATM蛋白将被纯化到足以进行三维结构和功能研究的数量。ATM蛋白在免疫球蛋白类别转换重组中的作用将通过用实验室开发的ATM核酶阻断mRNA表达来探索。这可能有助于解释A-T患者的选择性免疫缺陷和他们遭受的危及生命的复发性感染。最后，将开发定点突变并用于解释在患有A-T和其他疾病（如癌症）的患者中观察到的DNA变体的功能意义。性能现场=

EXCEED THE SPACE PROVIDED. This project seeks to improve the diagnosis and treatment of patients with ataxia-telangiectasia (A-T), a progressive and fatal neurological disease of childhood. A resource of well-characterized A-T patients is being established for future clinical trials. Affected haplotypes and the ATM mutations they carry will have been identified on a total of over 400 families of varying ethnic populations, with the hope that automated methods of mutation detection can soon be designed - based on this information. Haplotypes, mutations and phenotypes of -50 Hispanic-American families will be defined and compared to -150 other A-T families of Hispanic background, from Mexico, Central and South American, and Spain. Potential correlations between affected genotypes and phenotypes will be investigated, to identify new functional domains of the ATM protein and to improve our ability to predict the progress of the disease. Using a newly-established recombinant vaccinia virus expression system, the ATM protein will be purified in quantities sufficient for 3-dimensional structure and function studies. The role of the ATM protein in immunoglobulin class switch recombination will be explored by blocking the mRNA expression with an ATM ribozyme developed in the laboratory. This may help to explain the selective immunodeficiency of A-T patients and the life-threatening recurrent infections they suffer. Lastly, site directed mutagenesis will be developed and used to intrepret the functional significance of DNA variant observed in patients with A-T and other diseases, such as cancer. PERFORMANCE SITE ========================================Section End===========================================