Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing

T 淋巴细胞归巢的集成多尺度粘附动力学建模

• 批准号: 8803240
• 负责人: Daniel A Hammer
• 金额: $ 42.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803240
• 关键词: Adhesions; Adhesiveness; Adhesives; Affect; Affinity; Behavior; Blood; Blood Vessels; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cell Maturation; Cells; Code; Communication; Complex; Coupling; Cytoplasm; Data; Defect; Diacylglycerol Kinase; Docking; Engineering; Extravasation; Family; GTP-Binding Proteins; Glycerol Kinase; Goals; Health; Heterogeneity; Home environment; Homing; Human; Immune; Immune system; Immunity; Integrin Binding; Integrins; Jurkat Cells; Knock-out; Knockout Mice; LCP2 gene; Lead; Leukocytes; Ligand Binding; Ligands; Ligation; Location; Lymph; Lymphatic vessel; Lymphocyte; Lymphocyte Activation; Measures; Mechanics; Mediating; Methods; Modeling; Molecular; Mus; Pathway interactions; Pattern; Proteins; Receptor Signaling; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Stream; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Transfection; Travel; Work; adhesion receptor; base; cell behavior; cellular engineering; chemokine; chemokine receptor; computer framework; computerized tools; density; energy balance; gain of function; granulocyte; knock-down; leukocyte activation; mutant; novel; receptor; receptor expression; release of sequestered calcium ion into cytoplasm; research study; response; simulation; src Homology Region 2 Domain; tool; trafficking

DESCRIPTION (provided by applicant): The proper functioning of the immune system relies on T-lymphocytes to travel throughout the body and home to specialized tissues to transfer molecular information. Intimate molecular communication between cells is crucial to immune cells' maturation and activation. It has been established that lymphocyte trafficking from the blood stream and the lymphatic vessels into tissues is controlled by molecular "zip-codes" that identify the location where lymphocytes need to adhere. The zip-codes are precise, quantitative combinations of adhesion molecules and chemokines/chemokine receptor pairs on the lymphocyte and host tissue, such that when there is a "match", the lymphocyte responds by adhering rapidly. The goal of this proposal is to develop novel computational tools to understand how lymphocytes integrate and convert molecular signals into the activation of leukocyte integrins to mediate specific adhesion under flow. The basis of these tools is the integration of signal transduction networks, either involving chemokine activation of G-proteins networks or the assembly of the SLP-76 dependent "signalosome', into Adhesive Dynamics, a simulator of cell adhesion. This integrated method, called Integrated Signaling Adhesive Dynamics (ISAD) can readily predict the rate of lymphocyte firm adhesion under flow. The aims of this proposed work are to 1) extend our modeling of lymphocyte signal transduction networks to both chemokine signaling and the signalosome; 2) to integrate these models into ISAD simulations to simulate the progressive rolling and stopping of lymphocytes on defined molecular substrates; and 3) to compare our simulations with the adhesive behavior of engineered T- lymphocytes, including Jurkat cells and T cells from knock-out mice in which SLP-76 is deleted or altered, or in which diacylglycerol kinases (DGK) have been deleted. We show preliminary results that SLP-76 defects lead to a decrease in adhesiveness, and DGK defects lead to an increase in adhesiveness. The gain of function of DGK mutants is recapitulated by simulations, confirming the validity of our modeling. We will also measure and simulate how multiple chemokine signals are integrated within a single cell to give rise to adhesion, and how knock-downs of key signaling components both in T-cells and immortalized T-cells (Jurkat cells) lead to quantitative alterations in adhesion. Our comparison between simulation and experiment, and extensive sensitivity analysis, will allow us to identify ranges of parameter values consistent with experimental observations and to elucidate the key controlling pathways in lymphocyte adhesion and homing.

描述（由申请人提供）：免疫系统的正常运作依赖于 T 淋巴细胞在整个身体中移动并回到特定组织以传递分子信息。细胞之间密切的分子通讯对于免疫细胞的成熟和激活至关重要。已经确定，淋巴细胞从血流和淋巴管运输到组织中是由分子“邮政编码”控制的，该分子“邮政编码”识别淋巴细胞需要粘附的位置。邮政编码是淋巴细胞和宿主组织上粘附分子和趋化因子/趋化因子受体对的精确、定量组合，这样当存在“匹配”时，淋巴细胞就会通过快速粘附来做出反应。该提案的目标是开发新颖的计算工具，以了解淋巴细胞如何整合并将分子信号转化为白细胞整合素的激活，从而介导流动下的特异性粘附。这些工 1）将我们的淋巴细胞信号转导网络模型扩展到趋化因子信号传导和信号体； 2) 将这些模型集成到 ISAD 模拟中，以模拟淋巴细胞在定义的分子基质上的渐进滚动和停止； 3) 将我们的模拟与工程化 T 淋巴细胞的粘附行为进行比较，包括 Jurkat 细胞和来自基因敲除小鼠的 T 细胞，其中 SLP-76 被删除或改变，或者其中二酰基甘油激酶 (DGK) 已被删除。我们的初步结果表明，SLP-76 缺陷导致粘合性下降，而 DGK 缺陷导致粘合性增加。通过模拟重现了 DGK 突变体的功能增益，证实了我们模型的有效性。我们还将测量和模拟多个 趋化因子信号整合在单个细胞内以产生粘附，以及 T 细胞和永生化 T 细胞（Jurkat 细胞）中关键信号成分的敲除如何导致粘附的定量改变。我们对模拟和实验进行比较，以及广泛的敏感性分析，将使我们能够确定与实验观察一致的参数值范围，并阐明关键控制途径 淋巴细胞粘附和归巢。