Systems biology analysis of dendritic cell interactions with biomaterials

树突状细胞与生物材料相互作用的系统生物学分析

• 批准号: 8330263
• 负责人: JULIA E BABENSEE
• 金额: $ 19.09万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330263
• 关键词: Achievement; Address; Antigens; Biocompatible Materials; Cell Communication; Cell Maturation; Cells; Cues; Cytokine Signaling; Data; Data Set; Decision Making; Dendritic Cells; Devices; Engineering; Environment; Exposure to; Family; Future; Gatekeeping; Immune; Immune response; Immunity; Individual; Integrins; Least-Squares Analysis; Ligation; Maintenance; Measures; Mediating; Medical; Modeling; Motivation; Outcome; Output; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Phosphoproteins; Process; Production; Protein Dynamics; Reagent; Receptor Signaling; Research Project Grants; Role; Sampling; Sepharose; Signal Transduction; Signaling Molecule; Small Interfering RNA; Statistical Models; Stimulus; System; Systems Biology; Testing; Time; Tissue Engineering; Training; Vision; base; combinatorial; cytokine; extracellular; human disease; in vivo; next generation; novel; pathogen; prevent; receptor; receptor function; response; vaccine delivery

DESCRIPTION (provided by applicant): Engineering immune responses will enable achievement of the true potential of the next generation of medical treatments by addressing the significant barrier of the host response. The central role of dendritic cells (DCs) as gatekeepers to the initiation of immune responses and maintenance of tolerance renders the control of their phenotype particularly important in situations where immune responses can be harnessed in combination products, such as vaccine delivery systems or tissue engineering strategies. Using biomaterials, an integral component of these devices, to direct the host response is a powerful and visionary strategy. Babensee et al have demonstrated biomaterial-based control of DC phenotype with modulation of immune responses to co- delivered antigen in vivo. As such, DCs at opposite ends of the phenotypic spectrum, from immature (or tolerogenic) to mature, are desirable to either induce non-responsiveness /tolerance or enhance protective immunity, respectively. The receptor-based mechanisms by which DCs recognize and respond to biomaterials is unknown, however commonalities between the cytokine, integrin, and pattern recognition receptor(PRR)-induced cellular responses and biomaterial-induced DC maturation, suggest that DCs engage a combination of these external sensing receptor families to initiate phenotypic responses to biomaterials. Our overall hypothesis is that DCs recognize and respond to biomaterial stimuli using a combination of receptors, necessitating an integrative modeling approach to establish multiple receptor ligation signatures associated with DC phenotypes. The objectives of this proposal are to 1) develop a model of how DCs integrate information from multiple receptor families concurrently to elicit phenotypic plasticity and 2) use this model to elucidate the key receptor families used by DCs to recognize and respond to biomaterials. We will achieve an integrative understanding with a global view of DC responses to biomaterials, including synergistic interactions, which is not feasible looking at one pathway at a time. The approach used in this proposal is to treat the DC as a system with delivered stimuli/inputs, sampled intermediate signals, and measured outputs/responses to develop a statistical model. This proposal thus applies a previously employed systems biology approach, developed by Lauffenberger, Janes and Kemp, in a novel capacity of addressing the "inverse" problem of identifying receptors used by DCs to sense biomaterials. Specific aim 1 will establish an integrative model of signaling and cytokine profiles for known receptor-driven DC phenotypic outcomes. Specific aim 2 will identify the receptor basis for DC responses to specific biomaterials. Specific aim 3 will validate role of receptor families mediating DC responses to specific biomaterials. Completion of this project will provide a framework for informed engineering DC-driven immune responses in the context of biomaterials for future studies. It will also provide a context for in-depth study of individual receptors with a dominant role in DC responses to biomaterials.

描述（由申请人提供）：工程免疫反应将通过解决宿主反应的重大障碍，实现下一代医学治疗的真正潜力。树突状细胞（dc）作为启动免疫反应和维持耐受性的守门人，其核心作用使得在免疫反应可以在组合产品（如疫苗输送系统或组织工程策略）中利用的情况下，对其表型的控制尤为重要。使用生物材料作为这些装置的组成部分来指导宿主反应是一种强大而有远见的策略。Babensee等人已经证明了基于生物材料的DC表型控制与体内对共递送抗原的免疫反应的调节。因此，表型谱两端的dc，从未成熟（或耐受性）到成熟，分别是诱导无反应性/耐受性或增强保护性免疫的理想选择。DC识别和响应生物材料的基于受体的机制尚不清楚，但细胞因子、整合素和模式识别受体（PRR）诱导的细胞反应和生物材料诱导的DC成熟之间的共性表明，DC参与这些外部感知受体家族的组合，以启动对生物材料的表型反应。我们的总体假设是DC通过受体组合识别并响应生物材料刺激，因此需要综合建模方法来建立与DC表型相关的多受体连接特征。本提案的目标是：1)建立dc如何同时整合来自多个受体家族的信息以引发表型可塑性的模型；2)使用该模型阐明dc识别和响应生物材料所使用的关键受体家族。我们将从生物材料的全局视角对DC反应进行综合理解，包括协同相互作用，这是不可行的，一次只看一个途径。本提案中使用的方法是将DC视为具有传递刺激/输入，采样中间信号和测量输出/响应的系统，以开发统计模型。因此，该提案应用了Lauffenberger， james和Kemp开发的先前使用的系统生物学方法，以解决识别dc用于感知生物材料的受体的“逆向”问题的新能力。具体目标1将建立已知受体驱动的DC表型结果的信号传导和细胞因子谱的综合模型。特异性目标2将确定DC对特定生物材料反应的受体基础。特异性目的3将验证受体家族介导DC对特定生物材料反应的作用。该项目的完成将为未来研究生物材料背景下的dc驱动免疫反应提供一个知情的工程框架。这也将为深入研究在DC对生物材料的反应中起主导作用的个体受体提供背景。