The goal of the proposed research is the elucidation of the molecular mechanism by which low energy electromagnetic fields (EMF) initiate a cascade of cytoplasmic and nuclear signaling events in human lymphocyte precursor cells. We propose as our first major goal to elucidate the role of protein tyrosine kinases (PTK) in EMF-induced activation of the PKC- linked signaling pathways in normal as well as leukemic B-cell precursors corresponding to discrete developmental stages of human B-cell ontogeny. It si our central working HYPOTHESIS that EMF exposure results in rapid and sustained activation of Src family PTK and EMF-induced activation of PKC is triggered by stimulation of PTK. To test this hypothesis, we will first examine if EMF exposure of B-cell precursors will activate PTK prior to activation of PKC and PKC-dependent signaling pathways. Furthermore, we will examine the effects of tyrosine kinase inhibitors on EMF-induced activation of PKC and c-jun. We will next examine the effects of EMF on the enzymatic activity of the CD19-receptor associated Src family PTK in normal as well as leukemic B-cell precursors corresponding to discrete developmental stages of human B-cell ontogeny. The major HYPOTHESIS to be tested under SPECIFIC AIM 2 is that the low energy EMF will stimulate LYN kinase. This hypothesis will be tested using both the cell lines listed under Specific Aim 1 as well s primary leukemic blasts from children with ALL. We will also test the hypothesis that EMF-responsiveness in vitro will correlate with expression levels of CD19 receptor and CD19-associated LYN kinase activity, which is predicated upon the supposition that CD19 is the main EMF-sensitive target surface receptor on B-cell precursors.
Under SPECIFIC AIM 3, we will examine the relationship between the EMF- responsiveness of leukemic B-cell precursors and routinely measured disease or host-related laboratory parameters.
Under SPECIFIC AIM 4, we will examine the relationship between tyrosine kinase activity levels in ALL cells and the residential EMF measurements of patients from whom the cells were derived. We anticipate that the proposed research will clarify and improve the current knowledge of the biologic effects of low frequency EMF and their molecular mechanisms.
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| Kristupaitis, D; Dibirdik, I; Vassilev, A et al. (1998) Electromagnetic field-induced stimulation of Bruton's tyrosine kinase. J Biol Chem 273:12397-401 |
| Dibirdik, I; Kristupaitis, D; Kurosaki, T et al. (1998) Stimulation of Src family protein-tyrosine kinases as a proximal and mandatory step for SYK kinase-dependent phospholipase Cgamma2 activation in lymphoma B cells exposed to low energy electromagnetic fields. J Biol Chem 273:4035-9 |
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