Temporal & spatial organization of signaling complexes in T & B Cells

描述（由申请人提供）：本项目的总体目标是继续研究导致淋巴细胞发育、活化和恶性转化的信号转导事件的分子生物学和生物化学。此外，我们将研究信号模块，通常被认为是免疫细胞功能的调节剂，当在其他谱系中表达时，可能导致癌症的发展。该计划的项目是统一的，他们的利益在多分子复合物如何调节适当或病理信号的结果。因此，该计划的每个项目将以某种方式解决特定分子间相互作用如何调节细胞功能。该计划的三个项目是以前工作的延续，第四个项目是由一名研究人员领导的，他在我们最后一次资助期间加入了宾夕法尼亚大学的教师，并与我们的每一位研究人员进行了广泛的互动。项目1扩展了上一个资助期的工作，研究了含有76 kDa白细胞磷蛋白（SLP-76）的SH 2结构域及其相关分子作为淋巴细胞信号传导调节剂的作用。在这个项目中，重点将是如何SLP-76和它的伴侣蛋白的功能，以协调整合素激活T细胞和中性粒细胞。项目2是该计划的新项目，并研究了不在T细胞受体抗原接触部位而是在细胞远端形成的信号复合物。该计划的第三个项目将以前研究B细胞中免疫受体的工作扩展到新的观察结果，即上皮细胞中的这种信号可能导致恶性转化。该计划的最后一个项目是在先前研究Notch靶点的基础上进行的，以研究TRIBBL同系物2作为急性髓细胞性白血病关键诱导物的作用。这四个项目汇集了四个既定的研究人员，每个人都有蓬勃发展的个人研究项目，他们希望通过这种共同努力继续他们的互动。该计划将得到一个行政核心和两个科学核心的支持。第一个科学核心将有助于使用逆转录病毒转导方法分析关键信号分子的体内结构功能关系，进入骨髓或胎肝祖细胞。第二个科学核心由与我们项目相关的第五名研究人员领导，将继续提供图像分析方面的专业知识，协助每个项目可视化分子间复合物。这两个核心在第一个资助期内为我们每个研究人员的研究工作增加了很多。我们预计，我们的集体努力将提供新的见解，如何信号转导导致适当的细胞反应，以及这些过程如何可能出错，导致病理后果。

DESCRIPTION (provided by applicant): The overall goal of this Program is to continue investigations into the molecular biology and biochemistry of signal transduction events leading to lymphocyte development, activation, and malignant transformation. Additionally, we will be studying how signaling modules, typically thought of as regulators of immune cell function, when expressed in other lineages, may lead to development of cancer. The projects of this Program are united by their interests in how multimolecular complexes regulate either appropriate or pathologic signaling outcomes. Thus each project of the Program will address, in some way, how particular intermolecular interactions regulate cellular function. Three of the projects of this Program are continuations from previous work and the fourth project is led by an investigator who joined the faculty at Penn during the course of our last period of funding and who has interacted extensively with each of our investigators. Project 1 extends work from the last period of funding examining the role of SH2 domain containing leukocyte phosphoprotein of 76 kDa (SLP-76) and its associated molecules as regulators of lymphocyte signaling. In this project the emphasis will be on how SLP-76 and its partner proteins function to coordinate integrin activation in T cells and neutrophils. Project 2 is new to this Program and investigates signaling complexes which form not at the site of T cell receptor antigen contact but instead at the distal pole of the cell. The third project in this program extends previous work studying immunoreceptors in B cells to the novel observation that such signaling in epithelial cells may lead to malignant transformation. The final project of the Program follows on previous work examining targets of Notch to investigate the role of TRIBBL homolog 2 as a key inducer of acute myelogeneous leukemia. The four projects bring together four established investigators, each with thriving individual research programs, who wish to continue their interactions through this joint effort. The program will be supported by an Administrative Core and two Scientific Cores. The first Scientific Core will assist in analysis of in vivo structure function relationships of critical signaling molecules using a retroviral transduction approach into bone marrow or fetal liver progenitor cells. The second Scientific Core, led by a fifth investigator associated with our program, will continue to provide expertise in image analysis, assisting each project in visualizing intermolecular complexes. Both of these cores added a great deal to the research efforts of each of our investigators during the first period of funding. We anticipate that our collective efforts will provide new insights into how signals are transduced leading to appropriate cellular responses and how these processes may go awry leading to pathologic consequences.