Quantitative Study of T-cell Polarization

T 细胞极化的定量研究

• 批准号: 7257234
• 负责人: IVAN V MALY
• 金额: $ 26.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-03 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257234
• 关键词: Actins; Actomyosin; Adhesions; Antigen-Presenting Cells; Biomedical Research; Biomimetics; Cell Communication; Cell Shape; Cells; Cellular biology; Centrosome; Complex; Computer Simulation; Condition; Coupling; Data; Dimensions; Drug Formulations; Dynein ATPase; Experimental Models; Fiber; Golgi Apparatus; Grant; Immigration; Immune; Immune response; Immune system; Jurkat Cells; Kinesin; Kinetics; Knowledge; Lead; Life; Measurement; Mechanics; Methodology; Microscopy; Microtubules; Modeling; Molecular; Molecular Motors; Movement; Myosin ATPase; Numbers; Organelles; Outcome; Pathway interactions; Positioning Attribute; Process; Property; Quantitative Microscopy; Regulation; Research; Research Personnel; Surface; System; T-Lymphocyte; Testing; base; cell motility; design; migration; neoplastic cell; novel; research study

DESCRIPTION (provided by applicant): The objective of this project is to put our understanding of T cell polarization on a firm quantitative basis. T cells of the immune system polarize, i.e. orient themselves, toward their targets, such as infected or tumor cells to be eliminated. The crucial component of the T cell polarization is reorientation of the centrosome toward the target. Although a number of molecular pathways involved in regulation of this process have been identified, even a general understanding is lacking as to the mechanism of the process itself. New data lead us to hypothesize, contrary to the accepted notion, that the basic mechanism is whole-cell movement and deformation on contact with the target, a process directed toward whole-cell structural optimization. First, we will employ a simplified experimental system of T cells stimulated with planar biomimetic substrates to elucidate the basic features of the centrosome reorientation. This will be achieved through combination of computational modeling with quantitative, multidimensional, live-cell microscopy. Next, the contribution of specific force-generating intracellular processes (molecular motors, cytoskeletal dynamics) to the centrosome translocation will be determined by enriching the basic model with specific numerical models of these processes and comparing the predictions with experiments in which the specific molecular activities are modulated. Lastly, we will use the achieved understanding of the simplified system amenable to high- throughput measurements to extrapolate our knowledge computationally to the realistic case of the T cell- target cell interaction. The predictions will be tested by means of quantitative microscopy and the additional features found in the cell-cell interactions added to the computer model. The outcome of the project will be not only rigorous understanding of the biomedically significant phenomenon of centrosome polarization in the immune cells, formalized in a predictive computer model, but also a substantial empirical improvement of the new methodology of quantitative biomedical research.

描述（由申请人提供）：该项目的目标是将我们对 T 细胞极化的理解建立在坚实的定量基础上。免疫系统的 T 细胞会极化，即将自身定向到目标，例如受感染的细胞或要消除的肿瘤细胞。 T 细胞极化的关键组成部分是中心体向靶标重新定向。尽管已经确定了参与该过程调节的许多分子途径，但对该过程本身的机制还缺乏一般性的了解。新数据使我们假设，与公认的观点相反，基本机制是与目标接触时的全细胞运动和变形，这是一个针对全细胞结构优化的过程。首先，我们将采用平面仿生基质刺激的 T 细胞的简化实验系统来阐明中心体重新定向的基本特征。这将通过计算模型与定量、多维、活细胞显微镜相结合来实现。接下来，将通过用这些过程的特定数值模型丰富基本模型并将预测与调节特定分子活动的实验进行比较来确定特定的产生力的细胞内过程（分子马达、细胞骨架动力学）对中心体易位的贡献。最后，我们将利用对适合高通量测量的简化系统的理解，通过计算将我们的知识推断到 T 细胞-靶细胞相互作用的实际情况。这些预测将通过定量显微镜和添加到计算机模型中的细胞间相互作用中发现的附加特征进行测试。该项目的成果不仅是对免疫细胞中具有生物医学意义的中心体极化现象的严格理解（以预测计算机模型形式化），而且是对定量生物医学研究新方法的实质性改进。