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

描述(由申请人提供)：本计划的总体目标是继续研究导致淋巴细胞发育、激活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器，当在其他谱系中表达时，可能会导致癌症的发展。该计划的项目由于对多分子复合体如何调节适当的或病理的信号转导结果的兴趣而团结在一起。因此，该计划的每个项目都将以某种方式解决特定的分子间相互作用如何调节细胞功能。该计划的三个项目是先前工作的延续，第四个项目由一名研究人员领导，他在我们最后一期资助期间加入了宾夕法尼亚大学的教职员工，并与我们的每一名研究人员进行了广泛的互动。项目1扩展了上一个资助阶段的工作，研究了含有76 kDa白细胞磷蛋白(SLP-76)的SH2结构域及其相关分子作为淋巴细胞信号调节因子的作用。在这个项目中，重点将放在SLP-76及其伙伴蛋白如何发挥功能来协调T细胞和中性粒细胞中整合素的激活。项目2是该计划的新项目，它研究的信号复合体不是在T细胞受体抗原接触处形成的，而是在细胞的远端极形成的。该计划中的第三个项目将之前研究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工作的基础上研究Notch的靶点，以调查TRIBBL同源基因2作为急性髓细胞白血病的关键诱因的作用。这四个项目汇集了四个成熟的研究人员，每个人都有蓬勃发展的个人研究计划，他们希望通过这一联合努力继续他们的互动。该计划将由一个行政核心和两个科学核心提供支持。第一个科学核心将利用逆转录病毒转导方法将关键信号分子导入骨髓或胎儿肝脏祖细胞，帮助分析体内关键信号分子的结构、功能和关系。第二科学核心由与我们的计划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化合物。这两个核心都大大增加了我们每个研究人员在第一个资助阶段的研究努力。我们预计，我们的集体努力将提供新的见解，了解信号是如何传递的，从而导致适当的细胞反应，以及这些过程可能如何出错，从而导致病理后果。

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.