DMS/NIGMS 2: Regulation of Cellular Stemness during the Epithelial-Mesenchymal Transition (EMT)

DMS/NIGMS 2:上皮-间质转化 (EMT) 期间细胞干性的调节

基本信息

  • 批准号:
    2245957
  • 负责人:
  • 金额:
    $ 120万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-15 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

This research will involve a joint theoretical/experimental approach to address cell-fate trajectories that occur during induction of the epithelial-mesenchymal transition (EMT). The EMT transition was originally discovered in the context of developmental biology and refers to the fact that cells can dramatically change their phenotypic behavior from a sedentary, strongly-adherent lifestyle (“epithelial”) to one characterized by motility and weaker cell-cell coupling (“mesenchymal”). This transition was later shown to be directly relevant for the onset of metastatic spread of primary tumors. Recent efforts have indicated that epithelial cells can either undergo direct reprogramming to mesenchymal states or alternatively become more stem-like and exhibit intermediate, hybrid E/M properties. These latter states appear to be the most effective at initiating new tumors and hence the most dangerous. Based on the investigators’ preliminary investigations, state-of-the-art single cell measurement technology will be used together with advanced mathematical modeling frameworks to understand how cells choose specific fates and to quantitatively unravel the genetic and epigenetic dynamics that leads these cells along their particular trajectories. The investigators will develop new mathematical concepts such as the role of frustration in cell fate networks; here frustration refers to the incompatibility of various genetic interactions and understanding how it enables the aforementioned intermediate states can help develop ideas to interdict their effects. The investigators will also study the role of “epigenetic” modifiers, chemical modifications of proteins that help package the DNA that directly affect how easy it is to switch between different phenotypes. And, aside for the direct intellectual merit and possible spillovers into translational applications, this program will contribute the NSF’s “missing millions” goal by partnering with an HBCU to introduce this area of research to undergraduates from underrepresented groups.Technically, the projected research will consist of several interwoven areas coupling mathematics to biology. The investigators will take full advantage of modern single-cell technology to create datasets that will be used to quantitatively determine the step-by-step progress of EMT and concomitant stemness properties of cells, measuring both transcriptional profiles and features of the chromatin-dependent epigenetics. These data will help formulate new types of dynamical models, both deterministic and stochastic, coupling transcriptional regulation to a dynamically modifiable underling epigenetic landscape. These models will be used to understand the role of frustration, i.e. unsatisfied regulatory interactions in a given phenotypic state of the network, in the enabling of intermediate states with enhanced plasticity; this understanding could have direct translational relevance, as plasticity has been implicate in tumor initiation and in tumor therapy resistance. The data will also help develop and better understand the validity of advanced data analysis techniques such as the concept of optimal transport which allows for trajectory inference. This powerful idea requires the use of cost functions to relate data at different timepoints and the investigators will use both synthetic and actual data to explore the idea that incomplete mechanistic models can be used to create better such cost functions. All told, this research will greatly improve the understanding of cell-fate transitions and how they depend on the detailed molecular level underpinnings of genetic circuits governing transcriptional and translational processes and the epigenetic landscape to which these circuits are reciprocally coupled.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
这项研究将涉及一个联合的理论/实验方法,以解决细胞命运的轨迹,发生在诱导上皮-间充质转化(EMT)。EMT转变最初是在发育生物学的背景下发现的,并且是指细胞可以将其表型行为从久坐的、强粘附的生活方式(“上皮”)显著改变为以运动性和较弱的细胞-细胞偶联为特征的生活方式(“间充质”)。这种转变后来被证明与原发性肿瘤转移性扩散的发生直接相关。最近的研究表明,上皮细胞可以直接重编程为间充质状态,或者变得更像干细胞并表现出中间的混合E/M特性。这些后一种状态似乎在引发新肿瘤方面最有效,因此也是最危险的。基于研究人员的初步调查,最先进的单细胞测量技术将与先进的数学建模框架一起使用,以了解细胞如何选择特定的命运,并定量地揭示导致这些细胞沿着其特定轨迹的遗传和表观遗传动力学。研究人员将开发新的数学概念,例如挫折在细胞命运网络中的作用;这里挫折是指各种遗传相互作用的不相容性,了解它如何使上述中间状态能够帮助开发阻断其影响的想法。研究人员还将研究“表观遗传”修饰剂的作用,即蛋白质的化学修饰,这些修饰有助于包装DNA,直接影响在不同表型之间切换的容易程度。而且,除了直接的智力价值和可能的溢出效应转化为应用程序,该计划将有助于美国国家科学基金会的“失踪的数百万人”的目标,通过与HBCU合作,介绍这一领域的研究,以本科生从代表性不足的群体。技术上,预计的研究将包括几个交织的领域耦合数学生物学。研究人员将充分利用现代单细胞技术来创建数据集,这些数据集将用于定量确定EMT的逐步进展和细胞的伴随干细胞特性,测量转录谱和染色质依赖性表观遗传学的特征。这些数据将有助于制定新类型的动态模型,确定性和随机性,耦合转录调控的动态修改的基础表观遗传景观。这些模型将用于理解挫折的作用,即在网络的给定表型状态中不满意的调节相互作用,在具有增强的可塑性的中间状态的实现中;这种理解可能具有直接的翻译相关性,因为可塑性已经涉及肿瘤的起始和肿瘤治疗抗性。这些数据还将有助于开发和更好地理解先进数据分析技术的有效性,例如允许轨迹推断的最佳运输概念。这个强大的想法需要使用成本函数来关联不同时间点的数据,研究人员将使用合成数据和实际数据来探索不完整的机械模型可以用来创建更好的成本函数的想法。总而言之,这项研究将大大提高对细胞的理解,命运转变以及它们如何依赖于控制转录和翻译过程的遗传电路的详细分子水平基础,以及这些电路与之相互耦合的表观遗传景观。该奖项反映了NSF的法定使命,并通过使用基金会的智力价值和更广泛的影响审查进行评估,被认为值得支持的搜索.

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP).
  • DOI:
    10.1016/j.tranon.2023.101837
  • 发表时间:
    2024-01
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Catalanotto, Madison;Vaz, Joel Markus;Abshire, Camille;Youngblood, Reneau;Chu, Min;Levine, Herbert;Jolly, Mohit Kumar;Dragoi, Ana -Maria
  • 通讯作者:
    Dragoi, Ana -Maria
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Herbert Levine其他文献

Decoding leader cells in collective cancer invasion
集体癌症侵袭中对领导细胞的解码
  • DOI:
    10.1038/s41568-021-00376-8
  • 发表时间:
    2021-07-08
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Samuel A. Vilchez Mercedes;Federico Bocci;Herbert Levine;José N. Onuchic;Mohit Kumar Jolly;Pak Kin Wong
  • 通讯作者:
    Pak Kin Wong
Activity dependent modulation of synaptic transmission by presynaptic calcium stores: A dichotomy of short-term depression and facilitation
  • DOI:
    10.1186/1471-2202-14-s1-p351
  • 发表时间:
    2013-07-08
  • 期刊:
  • 影响因子:
    2.300
  • 作者:
    Suhita Nadkarni;Thomas Bartol;Herbert Levine;Terrence Sejnowski
  • 通讯作者:
    Terrence Sejnowski
Effects of Input Fluctuations on the Statistical Dynamics of a Biochemical Switch
  • DOI:
    10.1016/j.bpj.2011.11.869
  • 发表时间:
    2012-01-31
  • 期刊:
  • 影响因子:
  • 作者:
    Bo Hu;David A. Kessler;Wouter-Jan Rappel;Herbert Levine
  • 通讯作者:
    Herbert Levine
Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer
解码癌症中代谢与上皮间质转化的耦合决策
  • DOI:
    10.1038/s41416-021-01385-y
  • 发表时间:
    2021-04-15
  • 期刊:
  • 影响因子:
    6.800
  • 作者:
    Dongya Jia;Jun Hyoung Park;Harsimran Kaur;Kwang Hwa Jung;Sukjin Yang;Shubham Tripathi;Madeline Galbraith;Youyuan Deng;Mohit Kumar Jolly;Benny Abraham Kaipparettu;José N. Onuchic;Herbert Levine
  • 通讯作者:
    Herbert Levine
Machine learning meets physics: A two-way street.
机器学习与物理学的结合:一条双向路。

Herbert Levine的其他文献

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{{ truncateString('Herbert Levine', 18)}}的其他基金

Collaborative Research: International Physics of Living Systems Graduate Research Network
合作研究:国际生命系统物理学研究生研究网络
  • 批准号:
    2013949
  • 财政年份:
    2021
  • 资助金额:
    $ 120万
  • 项目类别:
    Continuing Grant
Spatial Patterning in the Progressing Tumor - The Role of Notch
进展性肿瘤中的空间模式——Notch 的作用
  • 批准号:
    1935762
  • 财政年份:
    2019
  • 资助金额:
    $ 120万
  • 项目类别:
    Continuing Grant
Ideas Lab Cracking the Olfactory Code: Followup PI Meeting (May 22, 2017); Arlington, VA
创意实验室破解嗅觉密码:后续 PI 会议(2017 年 5 月 22 日);
  • 批准号:
    1741669
  • 财政年份:
    2017
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Towards the design of Synthetic Cells
走向合成细胞的设计
  • 批准号:
    1748208
  • 财政年份:
    2017
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Workshop: Systems and Synthetic Biology for Designing Rational Cancer Immunotherapies; October 6-8, 2016, Tysons Corner, Virginia
研讨会:设计合理癌症免疫疗法的系统和合成生物学;
  • 批准号:
    1655161
  • 财政年份:
    2016
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Spatial Patterning in the Progressing Tumor - The Role of Notch
进展性肿瘤中的空间模式——Notch 的作用
  • 批准号:
    1605817
  • 财政年份:
    2016
  • 资助金额:
    $ 120万
  • 项目类别:
    Continuing Grant
NSF Ideas Lab - Cracking the Olfactory Code
NSF 创意实验室 - 破解嗅觉密码
  • 批准号:
    1546749
  • 财政年份:
    2015
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Conference: Dynamics Days 2015, January 9-11, 2015, Center for Theoretical Biological Physics, Houston, Texas
会议:2015 年动力学日,2015 年 1 月 9-11 日,理论生物物理中心,德克萨斯州休斯顿
  • 批准号:
    1503986
  • 财政年份:
    2015
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Physics of Wear, Tear, Aging and Failure in Living and Nonliving Systems Conference
生命和非生命系统中的磨损、撕裂、老化和故障物理学会议
  • 批准号:
    1544018
  • 财政年份:
    2015
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant
Workshop: Connecting the Biological and Physical Principles of Mammalian Aging; Arlington, VA; May 15-16, 2014
研讨会:连接哺乳动物衰老的生物学和物理原理;
  • 批准号:
    1442065
  • 财政年份:
    2014
  • 资助金额:
    $ 120万
  • 项目类别:
    Standard Grant

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DMS/NIGMS 1: Multilevel stochastic orthogonal subspace transformations for robust machine learning with applications to biomedical data and Alzheimer's disease subtyping
DMS/NIGMS 1:多级随机正交子空间变换,用于稳健的机器学习,应用于生物医学数据和阿尔茨海默病亚型分析
  • 批准号:
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合作研究:DMS/NIGMS 1:使用由细胞内张力传感测量提供的多尺度 3D 模型模拟细胞迁移
  • 批准号:
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  • 财政年份:
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  • 批准号:
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