Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment

人类细胞周期的计算模型揭示疾病机制并为治疗提供信息

基本信息

  • 批准号:
    10033514
  • 负责人:
  • 金额:
    $ 30.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-11 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT The overall goal of this project is to develop computational models that predict how the human cell cycle responds to clinically-relevant perturbations such as radiotherapy, targeted therapy, oncogenic mutation, and directed differentiation. These models will fill a significant void in our understanding of the mechanisms underlying the initiation, progression, and treatment of diseases that involve abnormal cell proliferation. Our approach is to use quantitative single-cell imaging to measure the molecular states of proliferating cells and to integrate these data into predictive modeling frameworks. We have assembled a cross-institutional team comprising a computational biologist, two cell biologists, and a physician scientist with specialization in radiation oncology. The team has a strong and productive history of collaboration with six joint publications to date. Aim 1 investigates the mechanism by which retinal epithelial cells respond to radiation-induced DNA damage during S phase to execute G2 arrest. Time-lapse imaging and deterministic modeling will predict: how the response to DNA damage is delayed until the S/G2 transition; how a small-molecule inhibitor of DNA repair—currently involved in clinical trial—intensifies the arrest response; and how loss of the tumor suppressor p53 renders cells refractory to combination therapy. Aim 2 asks how pancreatic epithelial cells with mutations in KRAS escape permanent cell cycle arrest. We will use high-content imaging to profile multiple signaling activities in single cells expressing oncogenic KRAS. These data will be used to construct a manifold representation of cell cycle progression that spans a two-week time course of oncogenic KRAS-mediated transformation. Computational analysis of the manifold’s geometry will identify molecular branching points in G1 that govern the proliferation/arrest decision in pancreatic cells, and we will validate these predictions through small molecules and genetic manipulation. Aim 3 tests the hypothesis that human embryonic stem cells inherit cell-cycle-specific gene products (specifically, G1 regulators) from the previous G2 phase to promote pluripotency in daughter cells. We will combine mitosis-specific chromatin profiling with convolutional neural network-based image analysis to identify the mechanisms by which stem cells sustain rapid proliferation and pluripotency over multiple cell-cycle generations. Each aim yields both basic and applied knowledge, providing fundamental insights into cell cycle progression under perturbation and generating specific, molecular predictions to inform new treatment schemes. With an eye toward the future, predictive models of the human cell cycle will enable patient-specific treatments for diseases that are driven by abnormal cell proliferation.
项目摘要/摘要

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Jeremy Purvis其他文献

Jeremy Purvis的其他文献

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{{ truncateString('Jeremy Purvis', 18)}}的其他基金

Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment
人类细胞周期的计算模型揭示疾病机制并为治疗提供信息
  • 批准号:
    10261500
  • 财政年份:
    2020
  • 资助金额:
    $ 30.71万
  • 项目类别:
Administrative Equipment Supplement for Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment
人类细胞周期计算模型的管理设备补充,以揭示疾病机制并为治疗提供信息
  • 批准号:
    10582092
  • 财政年份:
    2020
  • 资助金额:
    $ 30.71万
  • 项目类别:
Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment
人类细胞周期的计算模型揭示疾病机制并为治疗提供信息
  • 批准号:
    10458019
  • 财政年份:
    2020
  • 资助金额:
    $ 30.71万
  • 项目类别:
Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment
人类细胞周期的计算模型揭示疾病机制并为治疗提供信息
  • 批准号:
    10670944
  • 财政年份:
    2020
  • 资助金额:
    $ 30.71万
  • 项目类别:
UG Support Administrative Supplement: Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment
UG支持行政补充:人类细胞周期的计算模型揭示疾病机制并为治疗提供信息
  • 批准号:
    10810424
  • 财政年份:
    2020
  • 资助金额:
    $ 30.71万
  • 项目类别:
Controlling Stem Cell Fate through Computational Modeling
通过计算模型控制干细胞的命运
  • 批准号:
    9166324
  • 财政年份:
    2016
  • 资助金额:
    $ 30.71万
  • 项目类别:
Dynamics of cellular senescence in single human cells
单个人类细胞的细胞衰老动力学
  • 批准号:
    8724088
  • 财政年份:
    2012
  • 资助金额:
    $ 30.71万
  • 项目类别:
Dynamics of cellular senescence in single human cells
单个人类细胞的细胞衰老动力学
  • 批准号:
    8732676
  • 财政年份:
    2012
  • 资助金额:
    $ 30.71万
  • 项目类别:
Dynamics of cellular senescence in single human cells Admin Supplement
人类单个细胞的细胞衰老动力学管理补充
  • 批准号:
    8841972
  • 财政年份:
    2012
  • 资助金额:
    $ 30.71万
  • 项目类别:
Dynamics of cellular senescence in single human cells
单个人类细胞的细胞衰老动力学
  • 批准号:
    8353599
  • 财政年份:
    2012
  • 资助金额:
    $ 30.71万
  • 项目类别:

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24 小时活动周期在保护认知功能和预防阿尔茨海默病及相关痴呆方面的作用
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