Human T-cell leukemia virus type I (HTLV-I) is a pathogenic type C retrovirus that has been etiologically linked both to the adult T-cell leukemia (ATL) and to a chronic inflammatory disorder termed HTLV-I- associated myelopathy, or tropical spastic paraparesis, which is characterized by progressive central nervous system demyelination and intraocular inflammation, or uveitis. While the pathophysiologic mechanisms of altered T-cell regulation and proliferation observed in the setting of HTLV-I infection are only beginning to be elucidated, evidence increasingly supports a pivotal role for Tax, a 40 kDa HTLV-I-encoded transactivator protein that augments both viral and cellular gene expression. Importantly, HTLV-I Tax-induced expression of cellular genes does not involve a direct interaction between Tax and host DNA. Rather, Tax acts indirectly by altering or inducing the activity of various host transcription factors, including the NF-kappaB/Rel family of transactivators now known to be critically important in the regulation of an entire array of genes involved in T-cell growth, including genes encoding interleukin-2 (IL-2), the alpha subunit of the high-affinity IL- 2 receptor (IL-2Ra), GM-CSF, fos, and others. Recent studies have demonstrated that HTLV-I Tax-induced activation of NF-kappaB is preceded by the phosphorylation and degradation of IkappaBalpha, a cytoplasmic inhibitory protein that acts to sequester NF-kappaB in the host cytoplasm. However, the molecular mechanisms by which HTLV-I Tax induces phosphorylation of IkappaBalpha, and the subsequent functional consequences of IkappaBalpha phosphorylation with regard to IkappaBalpha degradation and NF-kappaB activation remain unclear. The candidate proposes to investigate the role of HTLV-I Tax-induced phosphorylation of IkappaBalpha in NF-kappaB activation. The following specific aims are presented: 1) To identify the sites of phosphorylation on IkappaBalpha induced in the presence of HTLV-I Tax, and the role of site-specific phosphorylation of IkappaBalpha in its degradation and the activation of nuclear NF-kappaB expression, 2) To identify the protein kinase(s) responsible for HTLV-I Tax-mediated phosphorylation of IkappaBalpha; and 3) To determine where in the cellular signaling cascade HTLV-I Tax acts to stimulate IkappaBalpha phosphorylation and degradation, and nuclear translocation of NF-kappaB. These studies should provide fundamental insights into the mechanisms of HTLV-I induced disease, including HTLV-I- associated uveitis. The candidate plans ultimately to apply the approaches and techniques learned during the five years of the training program to the study of infectious and immune-mediated eye disease.
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