Uncovering Basic Signaling Mechanisms in NK Cells in Mice and Humans

揭示小鼠和人类 NK 细胞的基本信号传导机制

基本信息

批准号：
8878729
负责人：
Jayajit Das
金额：
$ 45.47万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Natural Killer (NK) cells are lymphocytes of the innate immune system that defend us by lysing tumor and pathogen-infected cells. Recent experiments showed generation of long-lived "memory" NK cells in mouse and humans challenged by viral infections (such as CMV), similar to that of memory lymphocytes in the adaptive immune system. We seek to develop a quantitative mechanistic framework with predictive powers for signaling and activation in NK cells including "memory" NK cells in mice and humans by using a synergistic combination of in silico modeling and wet lab experiments. The in silico modeling rooted in statistical physics, non-linear dynamics, and multivariate statistics will be combined with standard biochemical and multi-parametric single cell mass cytometry (CyTOF mass cytometer) experiments on engineered human NK cell lines (NKLs), and naive and "memory" NK cells from mice and humans. We will investigate three overlapping aims: Aim 1: Develop a quantitative mechanistic framework for analyzing signaling and activation of NK cells stimulated by activating and inhibitory CMV-encoded ligands. Aim 2: Determine differences in signaling mechanisms between naive and "memory" NK cells in the mouse. Aim 3: Determine differences in signaling mechanisms between mouse and human "memory" NK cells. At the successful completion of the aims we will have a quantitative predictive mechanistic framework for studying NK cell signaling in mice and humans. The systems level knowledge gained from the proposed projects can also be applied in understanding mechanisms of activation regulated by heterogeneous receptor ligand interactions in other immune cells.

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫系统的淋巴细胞，通过裂解肿瘤和病原体感染的细胞来保护我们。最近的实验表明，在受到病毒感染（如 CMV）攻击的小鼠和人类中，会产生长寿的“记忆”NK 细胞，类似于适应性免疫系统中的记忆淋巴细胞。我们寻求通过计算机建模和湿实验室实验的协同组合，开发一种定量机制框架，对小鼠和人类的 NK 细胞（包括“记忆”NK 细胞）的信号传导和激活具有预测能力。植根于统计物理学、非线性动力学和多元统计的计算机建模将与工程化人类 NK 细胞系 (NKL) 上的标准生化和多参数单细胞质谱流式细胞仪 (CyTOF 质谱流式细胞仪) 实验相结合，来自小鼠和人类的“记忆”NK 细胞。我们将研究三个重叠的目标：目标 1：开发一个定量机制框架，用于分析通过激活和抑制 CMV 编码配体刺激的 NK 细胞的信号传导和激活。目标 2：确定小鼠中初始 NK 细胞和“记忆”NK 细胞之间信号传导机制的差异。目标 3：确定小鼠和人类“记忆”NK 细胞之间信号传导机制的差异。成功完成这些目标后，我们将拥有一个用于研究小鼠和人类 NK 细胞信号传导的定量预测机制框架。从拟议项目中获得的系统级知识也可以应用于理解其他免疫细胞中异质受体配体相互作用调节的激活机制。