EAGER: Dynamic Affinity for Regulation of Cell Signaling
EAGER:细胞信号传导调节的动态亲和力
基本信息
- 批准号:1330663
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-15 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
PI: Cheng DongProposal ID: 1330663Overview:The ability to understand cell-microenvironment communication is important in not only basic life science research, but also various biomedical applications such as cancer research and regenerative medicine. Because cell receptors are the major players for a cell to sense its microenvironment, the understanding of cell-microenvironment communication needs deep insights into molecular interactions between cell receptors and their ligands that can be cell receptors of another cell, free biomolecules, or extracellular matrix components. However, current understandings of these biomolecular interactions come primarily from the examination of the properties of cell receptors at a fixed or optimal functional state despite the dynamic nature of cell receptors and their ligands. Few if any studies have been carried out to understand how dynamic affinities drive intercellular communication that eventually regulates intracellular signaling pathways. Therefore, this proposal is aimed at exploring how dynamic affinity determines intracellular signaling by using both engineering and biological methods.Intellectual Merit:The objective of this proposal is to discover and understand a new mechanism for the regulation of cellular signaling transmission driven by dynamic affinities. To achieve this objective, CD82 and integrins will be used as a receptor model, and tumor cells and endothelial cells will serve as a cell model. Previous studies including those performed at PI's lab have suggeste that CD82 is associated with integrins that molecular interactions may influence cell phenotypes. However, it remains largely unknown on whether integrin binding affinities alter endothelial signaling due to a lack of experimental techniques to perform these analyses. Supported by these previous studies, it is hypothesized that increase of inducible CD82 expression decreases integrin-binding affinities, which inhibits tumor induced gap formation and tumor cell extravasation. Two high-risk tasks are proposed to validate this untested hypothesis. The first task aims to develop a new and innovative quasi-3D microscopy imaging technique to interrogate how integrin conformational states or binding affinities change with the level of CD82 expression. The second task is to understand how the dynamic change of integrin binding affinities determines intracellular signaling pathways and actin dynamics. It is expected that the study of this model system would lead to deep insights into the interactions between tumor cells and endothelial cells. Specifically, it will provide valuable insights into the mechanisms by which integrin-binding affinity affects endothelial cell strains in the actin cytoskeleton, protein kinase activity, and changes in VE-cadherin disassembly near the endothelial cell junctions over time.Broader Impacts:Education and outreach: The PI plans to build a new interdisciplinary research and education program, which aims to improve the participation of students at different levels, particularly underrepresented minorities and persons with disabilities in science and engineering. Students will be recruited through existing outreach programs from predominantly teaching institutions in Pennsylvania. Students will form research teams to develop computer programs, conduct laboratory work, analyze experimental results, write research papers, present findings in conferences, and maintain a web-based dissemination of results. Interdisciplinary and Transformative Traits: This high risk and high payoff project reflects a new paradigm, as prior studies were only focused on how binding affinities regulate cell adhesion rather than intramolecular cell signaling, which is the focus of this EAGER project. A new interdisciplinary research direction will be opened at the interface of engineering, biology, physiology, and biophysics. Importantly, the success of this proposal holds great potential to transform the ways that cell-cell communication is studied, and current / future bioengineering is developed for biomedical applications. Thus, the proposed research may not be viewed as "regular" questions or approaches, and has an appropriateness of the EAGER mechanism.
主要研究者:Cheng Dong Proposal ID:1330663概述:了解细胞微环境通信的能力不仅在基础生命科学研究中很重要,而且在各种生物医学应用中也很重要,如癌症研究和再生医学。由于细胞受体是细胞感知其微环境的主要参与者,因此对细胞-微环境通信的理解需要深入了解细胞受体及其配体之间的分子相互作用,这些配体可以是另一个细胞的细胞受体,游离生物分子或细胞外基质成分。然而,目前的理解,这些生物分子的相互作用主要来自检查的性质,细胞受体在一个固定的或最佳的功能状态,尽管细胞受体和它们的配体的动态性质。很少有研究来了解动态亲和力如何驱动细胞间通讯,最终调节细胞内信号通路。因此,本研究的目的是探索动态亲和性如何通过工程和生物学方法来决定细胞内信号传导。智力成果:本研究的目的是发现和理解动态亲和性驱动的细胞信号传导调控的新机制。为了实现这一目标,CD 82和整合素将被用作受体模型,肿瘤细胞和内皮细胞将被用作细胞模型。以前的研究,包括在PI的实验室进行的研究已经证实,CD 82与分子相互作用可能影响细胞表型的整合素相关。然而,由于缺乏进行这些分析的实验技术,整联蛋白结合亲和力是否会改变内皮信号传导在很大程度上仍然是未知的。在这些先前研究的支持下,假设诱导型CD 82表达的增加降低了整合素结合亲和力,这抑制了肿瘤诱导的间隙形成和肿瘤细胞外渗。提出了两个高风险的任务来验证这个未经检验的假设。第一个任务旨在开发一种新的和创新的准3D显微成像技术,以询问整合素构象状态或结合亲和力如何随CD 82表达水平而变化。第二个任务是了解整合素结合亲和力的动态变化如何决定细胞内信号传导途径和肌动蛋白动力学。该模型系统的研究将有助于深入了解肿瘤细胞和内皮细胞之间的相互作用。具体而言,它将提供有价值的见解整合素结合亲和力影响肌动蛋白细胞骨架中的内皮细胞株,蛋白激酶活性,以及随着时间的推移内皮细胞连接附近VE-钙粘蛋白分解的变化的机制。PI计划建立一个新的跨学科研究和教育计划,旨在提高不同层次学生的参与度,特别是在科学和工程领域代表性不足的少数民族和残疾人。学生将通过宾夕法尼亚州主要教学机构的现有外展计划招募。学生将组成研究团队开发计算机程序,进行实验室工作,分析实验结果,撰写研究论文,在会议上展示研究结果,并保持基于网络的结果传播。跨学科和变革性特征:这个高风险和高回报的项目反映了一种新的范式,因为以前的研究只关注结合亲和力如何调节细胞粘附,而不是分子内细胞信号传导,这是EAGER项目的重点。将在工程学、生物学、生理学和生物物理学的界面上开辟一个新的跨学科研究方向。重要的是,这一提议的成功具有巨大的潜力,可以改变细胞间通讯的研究方式,并为生物医学应用开发当前/未来的生物工程。因此,拟议的研究可能不会被视为“常规”的问题或方法,并具有适当的EAGER机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Cheng Dong其他文献
Deriving heterogeneous experts weights from incomplete linguistic preference relations based on uninorm consistency
基于一致一致性的不完全语言偏好关系推导异质专家权重
- DOI:
10.1016/j.knosys.2018.03.013 - 发表时间:
2018-06 - 期刊:
- 影响因子:8.8
- 作者:
Cheng Dong;Zhou Zhili;Cheng Faxin;Wang Juan - 通讯作者:
Wang Juan
Multi-Scale study on combustion acceleration and Self-Catalytic mechanisms of Nickel-Based energetic complex [Ni(Nsub2/subHsub4/sub)sub2/sub](Nsub3/sub)sub2/sub
镍基含能配合物[Ni(N₂H₄)₂](N₃)₂燃烧加速及自催化机制的多尺度研究
- DOI:
10.1016/j.fuel.2025.135134 - 发表时间:
2025-09-01 - 期刊:
- 影响因子:7.500
- 作者:
Cheng Dong;Shiyong Chen;Lixiao Shen;Tu Xu;Yinning Zeng;Yan Li;Zhenxin Yi;Chenguang Zhu;Lin Zhang;Shunguan Zhu - 通讯作者:
Shunguan Zhu
Polymer-based composites for electromagnetic interference shielding: principles, fabrication, and applications
用于电磁干扰屏蔽的聚合物基复合材料:原理、制备及应用
- DOI:
10.1016/j.compositesa.2025.108927 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:8.900
- 作者:
De Li;Cheng Dong;Ai Ping Zhang;Hai Lan Lin;Bi You Peng;Ke Yang Ni;Ke Cheng Yang;Jun Bian;Dai Qiang Chen - 通讯作者:
Dai Qiang Chen
Charge Density Wave and Crystal Structure of $$\hbox {K}_{x}\hbox {WO}_{3}$$ ( $$x=0.20$$ and 0.22) Prepared by Hybrid Microwave Method
- DOI:
10.1007/s10909-017-1762-6 - 发表时间:
2017-02-24 - 期刊:
- 影响因子:1.400
- 作者:
Runze Chen;Chaojun Gao;Kun Bu;Xiaoyu Hao;Zichen Wang;Lianjun Wen;Juan Guo;Mingju Chao;Erjun Liang;Lihong Yang;Cheng Dong - 通讯作者:
Cheng Dong
A least squares based diamond scheme for anisotropic diffusion problems on polygonal meshes
多边形网格上各向异性扩散问题的基于最小二乘的菱形方案
- DOI:
10.1002/fld.5031 - 发表时间:
2021-07 - 期刊:
- 影响因子:1.8
- 作者:
Cheng Dong;Tong Kang - 通讯作者:
Tong Kang
Cheng Dong的其他文献
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{{ truncateString('Cheng Dong', 18)}}的其他基金
Development of an interdisciplinary program in transforming computational science and engineering tools for cancer research
开发跨学科项目,转变癌症研究的计算科学和工程工具
- 批准号:
0729091 - 财政年份:2007
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
NIH-NSF BBSI: The Penn State Summer Institute (PSSI) for Biomaterials and Bio-nanotechnology
NIH-NSF BBSI:宾夕法尼亚州立大学生物材料和生物纳米技术夏季研究所 (PSSI)
- 批准号:
0234026 - 财政年份:2002
- 资助金额:
$ 20万 - 项目类别:
Continuing Grant
Molecular Dynamics in Tumor Cell Extravasation
肿瘤细胞外渗的分子动力学
- 批准号:
0138474 - 财政年份:2002
- 资助金额:
$ 20万 - 项目类别:
Continuing Grant
International Travel Grant: The First Korea-U.S. Joint Seminar on Biomedical Engineering
国际旅行补助金:首个韩美补助金
- 批准号:
9812245 - 财政年份:1998
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
CAREER: Faculty Early Career Development in Education and Research
职业:教师教育和研究领域的早期职业发展
- 批准号:
9502069 - 财政年份:1995
- 资助金额:
$ 20万 - 项目类别:
Continuing Grant
Micromechanics of Cell Activation in Cancer Metastasis
癌症转移中细胞激活的微观力学
- 批准号:
9308809 - 财政年份:1993
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
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