Ataxia-telangiectasia (A-T) is a human genetic disorder characterized by cerebellar degeneration leading to progressive neuromotor dysfunction, immunodeficiency, genomic instability, cancer predisposition, and profound sensitivity to ionizing radiation and radiomimetic chemicals. Ataxia-telangiectasia is caused by the absence or inactivation of the ATM protein, a multifunctional protein kinase that controls a myriad of nuclear and cytoplasmic signal transduction pathways, most notably those activated by DNA double-strand breaks. Some of ATM's functions may be tissue-specific. Cellular ATM is found in high molecular weight protein complexes, an indication of constant interaction with many other proteins. Identification of ATM's substrates and surrounding proteins are important keys to understanding its functions. This proposal is focused on the dissection of ATM-associated protein complexes, identification of their members, and delineation of their functional links to ATM. A large-scale, high throughput approach to isolation of ATM-containing protein complexes and identification of their members by mass-spectrometric analysis was successfully applied to cultured cell lines, leading to the identification of 15 ATM-associated proteins. While these proteins are being studied, the same approach will be applied to human and murine neuronal tissues and cell lines, in an effort to learn more about the functions of ATM in the central nervous system. The results are expected to lead to better understanding of Ataxia-telangiectasia and possibly to new treatment modalities for this disorder. Since Ataxia-telangiectasia is a multisystem disease, understanding its physiological basis is expected to have broad ramifications in various areas of medicine.
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