Preclinical Studies of Ataxia-Telangiectasia

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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===========================================