MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

自身免疫性疾病是一种病因广泛的衰弱疾病。 和效果。人们对其诱因知之甚少。关于中国传统文化的几点思考 人类自身免疫反应中涉及的机制很难 因为有众多的变数和后果，所以才能完成。 然而，小鼠品系，蚊子存活(MEV)，提供了一种极好的 在分子水平上研究自身免疫的系统。在这些 小鼠，致病的遗传原因是已知的-一个单一的突变 编码造血细胞蛋白酪氨酸磷酸酶的基因， PTP1C。磷酸酶在信号转导中起关键作用 通过细胞--从最表面的近端信号到远端信号 调节基因表达的转录因子的激活。我有过 发现转录因子NFkB表达异常 在MEV免疫细胞中，NFkB的反式激活亚单位p65不是 已找到-仅检测到p50和CREL。细胞质膜抑制因子 在MEV免疫细胞中也检测不到NFkB、IKB。这些发现是 新奇的，以前没有描述过的。为了更仔细地检查 导致这些蛋白质异常表达的机制， 将进行Northern杂交以确定这些基因的mRNA是否 蛋白质是转录的。在进一步的步骤中，降解率 NFkB/IKB蛋白和细胞核中新生mRNA的产生将是 已评估。PTP1C的作用与异常基因表达的关系 NFkB/IKB蛋白，PTP1C的转录将被阻断或减少， 利用反义技术，在正常表达NFkB/LKB的B细胞中， 并分析其对NFkB/IKB调控的影响。要检查 突变的PTP1C在MEV细胞中的作用及其信号的确定 转导通路中，这些细胞将被一些 刺激，通过不同的模式传递信号，以及对 计算了NFkB/IKB表达式。长期目标是定义一个模型 用于在自身免疫B细胞中诱导NFkB并利用它来靶向 潜在的治疗方法，如使用反义技术来减少 表达NFkB，减轻炎症反应。

Autoimmune diseases are debilitating disorders with wide ranges of causes and effects. Little is known about predisposing factors. A study of the mechanisms involved in an autoimmune response in humans is difficult to accomplish because of the multitude of variables and ramifications. However, the mouse strain, motheaten viable (mev), offers an excellent system in which to study autoimmunity at a molecular level. In these mice, the genetic cause for disease is known - a single mutation in a gene encoding a protein tyrosine phosphatase of hematopoietic cells, PTP1C. Phosphatases play critical roles in mediating signal transduction through a cell - from the most surface proximal signals to distal activation of transcription factors that regulate gene expression. I have discovered that the transcription factor, NFkB, is aberrantly expressed in mev immune cells; the transactivating subunit of NFkB, p65, is not found - only p50 and crel are detected. The cytoplasmic inhibitor of NFkB, IkB, is also not detectable in mev immune cells. These findings are novel and have not been previously described. To more closely examine the mechanisms responsible for the aberrant expression of these proteins, northern blots will be performed to determine whether mRNAs for these proteins are transcribed. In further steps, the degradation rates of NFkB/IkB proteins and nascent mRNA production in the nucleus will be evaluated. To correlate the role of PTP1C with the expression of aberrant NFkB/IkB proteins, transcription of PTP1C will be blocked or reduced, using antisense technology, in B cells which normally express NFkB/lkB, and the resulting effects on NFkB/IkB regulation assayed. To examine the effects of the mutant PTP1C in mev cells and define the signal transduction pathways, these cells will be activated with a number of stimuli, that transduce signals via different modes, and the effects on NFkB/IkB expression evaluated. Long term objectives are to define a model for induction of NFkB in autoimmune B cells and use this to target potential therapies such as employing antisense technology to reduce the expression of NFkB and alleviate the inflammatory response.