STUDIES OF RECEPTOR IMMUNOGLOBULIN MEDIATED SIGNALLING

虽然绝对需要受体免疫球蛋白介导的 信号传导还没有被证实用于激活静息B细胞， 来自各种来源的证据表明，至少在某些情况下， B细胞表面IG的交联是克隆扩增的先决条件 和差异化。 如果配体诱导受体IG介导的信号传导 导致激活的相关信号，人们会期望这样的 信号会驱动静止的GO-B细胞穿过特定的 沿着激活途径的限制点。 这样的B细胞会进入 一种激活的承诺状态，大概取决于随后的 用于增殖和分化的次级信号。 定义 受体IG在分子水平上产生的信号传导的作用将 大大增强了我们对关键信号的理解， GO期B细胞的活化以及进一步了解 受体介导的信号传导和细胞激活承诺点 一般来说，控制增长。 这项建议的目的是 研究受体IG介导的信号转导在 配体驱动的B淋巴细胞活化。 为了实现这一目标，我们建议 研究由配体-受体引起的特定分子变化 免疫球蛋白相互作用，并在功能水平上评估， 这些变化在一定程度上代表了B细胞中的特定承诺点 激活过程。 具体来说，我们将探讨配体的作用， 诱导受体交联刺激增加的表达， I-A α和I-E β基因以及c-myc原癌基因。 这些基因中每一个的表达的刺激增加已经被证实是有效的。 作为沿着B细胞活化途径的重要控制点 有丝分裂原系统，可能代表关键承诺点 在配体诱导的B细胞刺激中也是如此。 一旦确定了因果关系 受体IG占据或交联与表达之间的关系 对于这些基因产物，将进行功能研究， 证明I-A α、I-E β和c-myc增加的相关性 表达朝向更常规的B细胞活化标志， 增殖和免疫球蛋白分泌。 此外，我们建议 研究转导受体IG产生的机制 信号穿过质膜，以促进增加I-A α，I-E β和c-myc基因表达。 特别是，我们将定义 蛋白激酶C在信号转导途径以及 蛋白质-蛋白质关联可能在信号传导中很重要。

While an absolute requirement for receptor immunoglobulin mediated signaling has yet to be demonstrated for the activation of resting B cells, evidence from a variety of sources suggests that in at least some cases, crosslinking of B cell surface Ig is a prerequisite for clonal expansion and differentiation. If ligand induced receptor Ig mediated signalling results in relevant signals for activation, one would expect that such signaling would drive the resting, GO-B cell to traverse specific restriction points along the activation pathway. Such B cells would enter a state of commitment for activation, dependent presumably, on subsequent secondary signals for proliferation and differentiation. Definition of the role of receptor Ig generated signaling at the molecular level would greatly enhance our understanding of the critical signals required for activation of GO stage B cells as well as to further our understanding of receptor mediated signaling and activational commitment points for cell growth control in general. The objective of this proposal is to investigate the role and mechanism of receptor Ig mediated signaling during ligand driven B lymphocyte activation. To accomplish this, we propose to study specific molecular changes resulting from ligand-receptor immunoglobulin interaction and to assess at the functional level, to what extent these changes represent specific commitment points in the B cell activation process. Specifically, we will explore the role of ligand induced receptor crosslinking in the stimulation of increased expression of I-A alpha and I-E beta genes as well as the c-myc proto-oncogene. Stimulated increases in expression of each of these genes has been implicated as important control points along the B cell activation pathway in mitogen systems and are likely to represent critical commitment points in ligand induced B cell stimulation as well. Once establishing a causal relationship between receptor Ig occupancy or crosslinking and expression of these gene products, functional studies will be undertaken to demonstrate the relevance of increased I-A alpha, I-E beta and c-myc expression towards more conventional hallmarks of B cell activation such as proliferation and immunoglobulin secretion. In addition, we propose to investigate the mechanism(s) operative in transducing receptor Ig generated signals across the plasma membrane to facilitate increased I-A alpha, I-E beta and c-myc gene expression. In particular, we will define the role of protein kinase C in the signal transduction pathway as well as protein-protein associations that may be important in signaling.