PROTEIN TYROSINE KINASES AND ELECTROMAGNETIC FIELDS

拟议研究的目标是阐明 低能量电磁场（EMF）引发 人淋巴细胞胞质和核信号级联反应 前体细胞 我们提出的第一个主要目标是阐明 蛋白酪氨酸激酶（PTK）在EMF诱导的PKC激活中的作用 正常和白血病B细胞前体中的相关信号通路 对应于人类B细胞个体发育的离散发育阶段。 这是我们的中心工作假设，电磁场暴露的结果，在快速和 Src家族PTK的持续激活和EMF诱导的PKC激活， 由PTK的刺激引发。 为了验证这一假设，我们将首先 检查B细胞前体的EMF暴露是否会在 PKC和PKC依赖性信号通路的激活。 而且我们 将检查酪氨酸激酶抑制剂对EMF诱导的 我们接下来将研究电磁场对PKC和c-jun激活的影响。 CD 19-受体相关Src家族PTK的酶活性在 正常以及白血病B细胞前体对应于离散的 人类B细胞个体发育的发育阶段。 主要假设是 在特定目标2下测试的是低能量EMF将刺激林恩 激酶。 将使用列出的两种细胞系检验该假设 在特定目标1下，以及来自患有 所有. 我们还将测试的假设，电磁场反应在体外 将与CD 19受体和CD 19相关 林恩激酶活性，这是基于CD 19是 B细胞前体上的主要EMF敏感靶表面受体。 下 具体目标3，我们将研究EMF之间的关系- 白血病B细胞前体的反应性和常规测量的疾病 或宿主相关的实验室参数。 根据具体目标4，我们将 检查ALL中酪氨酸激酶活性水平之间的关系 细胞和患者的住宅EMF测量， 是衍生的。 我们预计，拟议的研究将澄清和 提高目前对低频电磁场生物效应的认识 及其分子机制。

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.