Temporal/Spatial Organization of Signaling in T&B Cells

描述(申请人提供)：本项目的总体目标是对导致淋巴细胞发育、激活和凋亡的信号转导事件的分子生物学和生物化学进行研究。许多实验室最近的工作表明，多分子信号复合体的空间和时间组织在调控这些细胞过程中发挥着关键作用。因此，本计划中的每个项目都将以某种方式解决分子间相互作用在调节淋巴细胞功能中的作用。两个项目将专注于T淋巴细胞，两个项目将解决B细胞中的相关问题。项目1描述了检测适配蛋白SLP-76作为T细胞发育和T细胞激活调节因子的结构/功能关系的实验。第二个项目将研究Pleckstrin，一种高度丰富的淋巴细胞蛋白，如何影响细胞骨架重组。该计划的第三和第四个项目将侧重于B淋巴细胞。项目3将研究B细胞抗原受体在不与配体结合时如何传递信号，而第四个项目将研究 Notch蛋白在B细胞发育和凋亡中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，他们希望通过这种联合努力使他们的互动正规化。该方案将得到一个行政核心和两个科学核心的支持。第一个科学核心将帮助分析体内关键信号分子的结构/功能关系，使用逆转录病毒转导方法进入骨髓前体细胞。第二个科学核心由与我们的计划有关的第五名研究人员领导，将提供图像分析方面的专业知识，帮助每个项目可视化分子间化合物。我们预计，我们的集体努力将为淋巴细胞生物学提供新的见解，并有望为调节免疫细胞功能的新型治疗干预提供线索。

DESCRIPTION (provided by applicant): The overall goal of this Program is to conduct investigations into the molecular biology and biochemistry of signal transduction events leading to lymphocyte development, activation, and apoptosis. Recent work from many laboratories has demonstrated that the spatial and temporal organization of multimolecular signaling complexes plays a critical role in the regulation of each of these cellular processes. Accordingly, each project in this Program will address, in some way, the role of intermolecular interactions in the regulation of lymphocyte function. Two projects will focus on T lymphocytes and two projects will address related questions in B cells. Project 1 describes experiments examining the structure/function relationships of the adapter protein SLP-76 as a regulator of T cell development and T cell activation. The second project will investigate how pleckstrin, a highly abundant lymphocyte protein, impacts cytoskeletal reorganization. The third and fourth projects of this Program will focus on B-lymphocytes. Project 3 will investigate how the B cell antigen receptor transduces signals when not bound by ligand while the fourth project will address the role of Notch proteins in B cell development and apoptosis. The four projects bring together four established investigators, each with thriving individual research programs who wish to formalize 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 progenitor cells. The second scientific core, led by a fifth investigator associated with our Program, will provide expertise in image analysis, assisting each project in visualizing intermolecular complexes. We anticipate that our collective efforts will provide new insights into lymphocyte biology and will hopefully provide clues for novel therapeutic interventions to modulate immune cell function.