Morphogen Systems: A Math /Experimental Investigation

描述（由申请人提供）：发育生物学的主要目标是了解胚胎中结构和细胞类型的精确位置是如何指定的。这种组织模式的大部分是由形态发生素（morphogens）协调的，形态发生素是一种可扩散的分子，在不同的浓度下对细胞命运产生不同的影响。在许多情况下，组织模式化与形态发生梯度的作用一致，形态发生梯度指示细胞根据其在空间中的位置采取不同的命运。这种依赖于位置的命运分配是图案化系统的基本特征。在这里，我们建议通过一个综合的数学和实验方法的程序来调查形态发生信号和模式的形成。我们将超越现象学建模，明确纳入特定的生物过程-受体结合和解离，受体的内/胞吐，降解，形态发生和受体合成的反馈调节等-从实验中得知它们会影响形态发生素介导的图案形成。我们的最终目标是发展定量的，机械的，和实验验证的理论信号和基因转录的基础模式的形成。 基于已知生物学过程的形态发生素介导的模式化的定量理论将促进我们对基础发育生物学的理解，也可能导致对其他复杂生物系统的应用，如信号传导和基因调控网络。这些应用的结果可能有助于理解和解决许多类型的人类发育异常。

DESCRIPTION (provided by applicant): A major goal of developmental biology is to understand how the precise locations of structures and cell types in the embryo are specified. Much of this tissue patterning is orchestrated by morphogens, diffusible molecules that exert qualitatively different effects on cell fate at different concentrations. In many cases, tissue patterning is consistent with an action of morphogen gradients that instruct cells to adopt different fates as a function of their location in space. Such position-dependent assignment of fates is an essential feature of a patterning system. Here we propose to investigate morphogen signaling and pattern formation through an integrated program of mathematical and experimental approaches. We will go beyond phenomenological modeling and explicitly incorporate specific biological processes-receptor binding and dissociation, endo/exocytosis of receptors, degradation, feedback regulation of morphogen and receptor synthesis, etc.--that are known from experiments to influence morphogen-mediated patterning. Our ultimate goal is to develop quantitative, mechanistic, and experimentally testable theories of the signaling and gene transcription that underlie pattern formation. Quantitative theories of morphogen-mediated patterning that are based on known biological processes will advance our understanding of fundamental developmental biology, and may also lead to applications to other complex biological systems, such as signaling and gene-regulatory networks. The results from these applications may help to understand and address many types of human developmental abnormalities.