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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8878729
• 关键词: Agonist; Antibodies; B-Lymphocytes; Biochemical; Biochemical Reaction; Cell Line; Cells; Cellular biology; Code; Collection; Computer Simulation; Cytolysis; Cytomegalovirus; Cytomegalovirus Infections; Cytometry; Data; Development; Entropy; Generations; Guidelines; Health; Heterogeneity; Human; Human Engineering; Immune; Immune system; Immunologic Memory; Infection; Kinetics; Knowledge; Life; Ligands; Lymphocyte; Memory; Methods; Modeling; Molecular; Mus; NK Cell Activation; Natural Killer Cells; Noise; Nonlinear Dynamics; Outcome; Physics; Plant Roots; Principal Component Analysis; Proteins; Receptor Signaling; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Virus Diseases; base; design; interdisciplinary approach; pathogen; receptor; research study; response; secondary infection; statistics; tumor

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，通过溶解肿瘤和病原体感染的细胞来保护我们。最近的实验表明，在病毒感染（如CMV）的小鼠和人类中产生长寿的“记忆”NK细胞，类似于适应性免疫系统中的记忆淋巴细胞。我们试图通过使用计算机模拟和湿实验室实验的协同组合，开发一种定量机制框架，该框架具有对小鼠和人类NK细胞（包括“记忆”NK细胞）中信号传导和活化的预测能力。植根于统计物理学、非线性动力学和多变量统计学的计算机模拟建模将与标准生物化学和多参数单细胞质量细胞计数（CyTOF质量细胞计数器）实验相结合，该实验对工程化的人NK细胞系（NKL）以及来自小鼠和人的幼稚和“记忆”NK细胞进行。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，用于分析激活和抑制CMV编码的配体刺激的NK细胞的信号传导和激活。目的2：确定小鼠中幼稚和“记忆”NK细胞之间信号传导机制的差异。目的3：确定小鼠和人类“记忆”NK细胞之间信号传导机制的差异。在目标的成功完成，我们将有一个定量的预测机制框架，研究小鼠和人类的NK细胞信号。从所提出的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由异质性受体配体相互作用调节的激活机制。

项目成果

Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes.

受体和信号分子的空间聚集调节 NK 细胞对肽库变化的反应。

• DOI: 10.3389/fimmu.2019.00605
• 发表时间: 2019
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Mbiribindi,Berenice;Mukherjee,Sayak;Wellington,Dannielle;Das,Jayajit;Khakoo,SalimI
• 通讯作者: Khakoo,SalimI