Integrated behavior of molecular regulatory networks

分子调控网络的综合行为

基本信息

  • 批准号:
    6950187
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

A. Understanding the behavior of bioregulatory networks is critical for future progress in biology and therapeutics. The complexity and high interconnectivity of these networks however often makes it difficult to comprehend directly how the system functions. Understanding of function will often require simulation by computer. It is questionable however whether the present state of knowledge is sufficient for computational simulations of large systems to yield useful results. We took an alternative approach, based on the notion that essential behavior is already encoded in simple subsystems, and that further complexity serves to modulate this behavior. This possibility is attractive from considerations of evolution and system robustness. A second premise for the current investigation is that the response characteristics of the fundamental subsystems are often switch-like. This theoretical approach, to the degree that it may be successful, will facilitate linkage between theory and experiment. Subsystems characterized by a combination of theory and experiment could then be combined to model larger networks. The subject of our investigation was the network that controls the induction of a set of genes in response to hypoxia. This was an attractive subject for theoretical study, because extensive (albeit yet incomplete) information has accumulated about relevant molecular and biological behavior, and because there is a clearly defined dependence of an output on an input. The input is the concentration of molecular oxygen, and the output is the activation of promoters that are under the control of hypoxia-regulated elements (HRE). We showed how a model ("core") subsystem can be selected from a molecular interaction map, how it can be encoded for computer survey of parameter space, how switch-like behavior can be found, and how the results may predict or guide experiments. A manuscript describing this work has been prepared. B. In a study of gene expression changes associated with a drug resistant cell line we encountered a pattern of seemingly paradoxical changes consistent with the hypothesis that multi-drug resistance could primarily involve the development of a defect in apoptosis (recently published: Reinhold et al. 2003 Cancer Res.). The hypothesis, which we call "permissive apoptosis resistance," also entails gene expression changes that promote cell proliferation but that would induce apoptosis were it not for a primary apoptosis defect. Our study compared a human prostate cancer cell line (DU145) with a subline that had been selected for resistance to a camptothecin. cDNA microarray analysis of 1,648 cancer-related genes disclosed expression differences in 181 of these genes. Among these 181 genes, there were a larger than expected number of the apoptosis-related genes, suggesting a general defect in the apoptosis machinery. Indeed, the resistant line displayed reduced apoptotic responses to several agents other than camptothecin, including cisplatin, staurosporine, UV, ionizing radiation, and serum deprivation. Closer examination of the gene expression changes however disclosed the surprising fact that many of the changes were in the wrong direction for apoptosis resistance. In order to make sense of this surprising pattern, we charted the altered genes in a molecular interaction map, using the symbols defined by Kohn (1999 Mol. Biol. Cell). What emerged is that almost all of the genes altered in the expected direction fell into one of two categories. Most were in the downstream core apoptosis network, including the genes BAD, caspase-6, and some associated genes, while some were regulators of the key survival kinase, Akt/PKB. On the other hand, nearly all of the genes altered in the contrary direction were in pathways that impact both apoptosis and cell proliferation, including c-Myc, E2F1, and players in the NFkB and TGFb pathways. The changes in the drug-resistant cells were nearly always such that they would be expected to enhance both apoptosis and cell proliferation. These findings suggested a model ("permissive apoptosis resistance") as one route by which cells could acquire multi-drug resistance. According to this model, cells would first be selected for one or more defects in the core apoptosis network, i.e., in genes that function primarily to control or execute apoptosis. When this defect is in place, the cells would then be free to acquire other gene expression changes that would enhance proliferation, but that would also have induced apoptosis were it not for the downstream defect.
A.了解生物调控网络的行为对于生物学和治疗学的未来进展至关重要。然而,这些网络的复杂性和高度互连性往往使人们难以直接理解系统的功能。对功能的理解往往需要计算机模拟。然而,目前的知识水平是否足以对大型系统进行计算模拟,以产生有用的结果,这是值得怀疑的。我们采取了另一种方法,其基础是基本行为已经编码在简单的子系统中,并且进一步的复杂性有助于调节这种行为。从进化和系统鲁棒性的考虑来看,这种可能性是有吸引力的。当前研究的第二个前提是,基本子系统的响应特性通常是开关式的。这种理论方法,在一定程度上,它可能是成功的,将促进理论和实验之间的联系。以理论和实验相结合为特征的子系统可以结合起来,对更大的网络进行建模。 我们研究的主题是控制一组基因响应缺氧诱导的网络。这是一个有吸引力的理论研究课题,因为大量的(尽管还不完整)信息积累了相关的分子和生物学行为,因为有一个明确定义的依赖于输入的输出。输入是分子氧的浓度,输出是在低氧调节元件(HRE)控制下的启动子的激活。 我们展示了如何从分子相互作用图中选择模型(“核心”)子系统,如何对它进行编码以用于参数空间的计算机调查,如何发现开关样行为,以及结果如何预测或指导实验。描述这项工作的手稿已经准备好。 B。在一项与耐药细胞系相关的基因表达变化研究中,我们发现了一种看似矛盾的变化模式,这与多药耐药可能主要涉及细胞凋亡缺陷的发展这一假设一致(最近发表:Reinhold et al. 2003 Cancer Res.)。我们称之为“容许性凋亡抵抗”的假说也需要基因表达的变化,这些变化促进细胞增殖,但如果不是由于原发性凋亡缺陷,则会诱导凋亡。 我们的研究比较了人前列腺癌细胞系(DU 145)与已被选择为耐喜树碱的亚系。对1,648个癌症相关基因的cDNA微阵列分析揭示了其中181个基因的表达差异。在这181个基因中,凋亡相关基因的数量比预期的要多,表明凋亡机制中存在普遍缺陷。事实上,耐药细胞系显示出对喜树碱以外的几种药物(包括顺铂、星形孢菌素、UV、电离辐射和血清剥夺)的凋亡反应降低。然而,对基因表达变化的更仔细检查揭示了令人惊讶的事实,即许多变化是在细胞凋亡抗性的错误方向上。 为了理解这种令人惊讶的模式,我们在分子相互作用图中绘制了改变的基因,使用Kohn(1999 Mol. Cell)。结果发现,几乎所有基因都按照预期的方向发生了改变,这些基因可以分为两类。大多数位于下游核心凋亡网络中,包括基因BAD,caspase-6和一些相关基因,而一些是关键存活激酶Akt/PKB的调节因子。另一方面,几乎所有以相反方向改变的基因都在影响细胞凋亡和细胞增殖的途径中,包括c-Myc,E2 F1以及NFkB和TGF β途径中的参与者。耐药细胞中的变化几乎总是这样,即它们预期会增强细胞凋亡和细胞增殖。 这些发现提示了一种模型(“允许性凋亡抗性”)作为细胞获得多药耐药性的一种途径。根据该模型,细胞将首先被选择用于核心凋亡网络中的一个或多个缺陷,即,在主要控制或执行细胞凋亡的基因中。当这种缺陷存在时,细胞就可以自由地获得其他基因表达的变化,这些变化会增强增殖,但如果没有下游缺陷,也会诱导凋亡。

项目成果

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KURT KOHN其他文献

KURT KOHN的其他文献

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{{ truncateString('KURT KOHN', 18)}}的其他基金

Investigations on the integrated behavior of molecular r
分子r整合行为的研究
  • 批准号:
    7337939
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigating Regulatory Networks that Control Cell Proliferation and Apoptosis
研究控制细胞增殖和凋亡的调控网络
  • 批准号:
    7965093
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigating Regulatory Networks that Control Cell Proliferation and Apoptosis
研究控制细胞增殖和凋亡的调控网络
  • 批准号:
    8157200
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigations on the integrated behavior of molecular r
分子r整合行为的研究
  • 批准号:
    7048175
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Gene expression relationships in human cancer tissues and cell lines.
人类癌症组织和细胞系中的基因表达关系。
  • 批准号:
    9154024
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigations on the integrated behavior of molecular regulatory networks that
分子调控网络整合行为的研究
  • 批准号:
    6433077
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigating Regulatory Networks that Control Cell Proliferation and Apoptosis
研究控制细胞增殖和凋亡的调控网络
  • 批准号:
    8348900
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigating Regulatory Networks that Control Cell Proliferation and Apoptosis
研究控制细胞增殖和凋亡的调控网络
  • 批准号:
    8937652
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
INVESTIGATIONS ON THE INTEGRATED BEHAVIOR OF MOLECULAR REGULATORY NETWORKS THAT C
分子调控网络综合行为研究
  • 批准号:
    6289180
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Investigating regulatory networks that control cell proliferation and apoptosis
研究控制细胞增殖和凋亡的调控网络
  • 批准号:
    7732912
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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