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A quantitative study of Drosophila apoptosis within and across single cells.

机译：定量研究果蝇在单个细胞内和细胞间的凋亡。

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摘要

Apoptosis is essential for normal physiology, such as development, maintenance and aging among metazoans. Drosophila melanogaster is an excellent model organism for the study of developmental apoptosis because it is genetically tractable, and the essential apoptosis mechanisms are conserved in this organism.;The validation of laboratory experiments is often done capturing images of cells and cell activity in vitro, or directly in vivo when possible. The apoptotic removal of the wing epithelium in Drosophila is a favored example because it can be easily imaged. The underlying mechanisms that govern this developmental stage are still unclear. However, the proper quantification of the apoptotic removal, especially from a spatiotemporal perspective, can aid the study of apoptosis in a population of cells, at the tissue or organ level.;Despite the striking similarity in the apoptosis pathways of fruit flies and mammals, differences have emerged. Because of these differences in the apoptosis pathway of the two species, we compiled a new model of the Drosophila apoptosis pathway. We discovered a previously unmentioned positive feedback loop between initiator and effector caspases. Through bifurcation analysis we confirmed its relationship with the characteristic all-or-none switching activity, often described with reference to apoptosis.;One of the more important issues, when modeling a population of cells, is the cell-to-cell response variability that is noticed in the population. We investigated the intrinsic stochasticity of the genetic models represented by activating and inhibitory Hill functions, using five different methods. We applied the stochastic simulation algorithm and the linear noise approximation methods to the full-scale elementary-reaction models that are expanded from the respective Hill functions. For comparison, we used the heuristic reduction methods that apply the quasi-steady-state approximation to simplify the full-network models. A more innovative method, the slow-scale linear noise approximation method was also applied. All three linear noise approximation methods show much faster computational speed when compared to the stochastic simulation algorithm counterparts. The full-scale and the slow-scale linear noise approximation compute the correct levels of intrinsic noise. The slow-scale linear noise approximation, however, achieves the same level of accuracy with considerably higher computational efficiency.
机译：细胞凋亡对于后生动物的正常生理至关重要，例如发育，维持和衰老。果蝇（Drosophila melanogaster）是一种研究发育性凋亡的优秀模型生物，因为它具有遗传易处理性，并且在该生物中保留了重要的凋亡机制。;实验室实验的验证通常是通过在体外捕获细胞和细胞活性的图像来完成的，或者尽可能直接在体内。果蝇中翼状上皮的凋亡去除是一个受欢迎的例子，因为它很容易成像。尚不清楚控制该发育阶段的潜在机制。然而，对凋亡清除的正确定量，特别是从时空的角度来看，可以帮助研究组织或器官水平的细胞群体的凋亡。尽管果蝇和哺乳动物的凋亡途径具有惊人的相似性，差异已经出现。由于两个物种的凋亡途径存在这些差异，我们建立了果蝇凋亡途径的新模型。我们发现了启动子和效应子胱天蛋白酶之间先前未提及的正反馈回路。通过分叉分析，我们证实了其与特征性的全有或全无转换活性之间的关系，通常与凋亡有关。;在对细胞群进行建模时，更重要的问题之一是细胞间应答变异性在人群中被注意到。我们用五种不同的方法研究了以激活和抑制希尔函数为代表的遗传模型的内在随机性。我们将随机模拟算法和线性噪声近似方法应用于从各自的希尔函数扩展的满量程基本反应模型。为了进行比较，我们使用了启发式约简方法，该方法采用准稳态近似来简化全网络模型。还应用了一种更创新的方法，即慢速线性噪声近似方法。与随机仿真算法相比，所有三种线性噪声逼近方法均显示出更快的计算速度。满量程和慢量程线性噪声近似值可计算出正确的固有噪声水平。但是，慢速线性噪声近似可以以相当高的计算效率实现相同的精度水平。

著录项

  • 作者

    Ziraldo, Riccardo.;

  • 作者单位

    The University of Texas at Dallas.;

  • 授予单位 The University of Texas at Dallas.;
  • 学科 Biomedical engineering.;Applied mathematics.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 康复医学;
  • 关键词

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