BIOCOMPLEXITY--Multiscale Simulation of Avian Limb Development

发育中的多细胞生物体在形状和形式上发生了巨大的变化，并出现了迅速变化的专门(分化)细胞类型的空间组织，例如神经元和肌肉纤维。这些事件产生了身体计划和各种器官，依赖于调控的基因表达，细胞之间的复杂相互作用，以及细胞的协调运动。基因表达本身不能完全解释身体计划、特定形式和形状的出现。遗传学和生物化学在发育过程中与单个细胞和细胞团的物理性质相互作用，使其成为一个极其复杂的多尺度过程。然而，就像在许多复杂的过程中一样，如果使用适当的技术来分析发育中的有机体，人们可以在不同的层面上发现动态和组织规则。这个项目汇集了生物学家、实验和理论物理学家、数学家和计算机科学家，他们每个人都有分析个别生物物理问题的经验，并将他们的专业知识应用于特定的发育过程--脊椎动物肢体的形成。实验和理论方法将被用来研究肢芽从体壁中的出现，介导细胞聚集的基因的控制，肢体骨骼模式的时空调节，以及神经纤维从脊髓进入肢体。这项工作将导致包括亚细胞，细胞和超细胞机制的多层次表征，这将提供对脊椎动物肢体发育的因果理解，并产生可用于研究发育生物学中类似问题的分析工具。这些工具将包括用于求解不可避免的复杂数学方程系统的软件，这些数学方程系统描述了在活胚胎中发现的遗传和材料属性的相互作用。将建立和分发新的软件，不仅模拟肢体发育，还模拟其他类型的器官形成和疾病(例如肿瘤转移和血管形成)。总体战略代表着朝着真正整合动物发育研究的方向迈出了一步，以兑现过去十年基因测序项目的承诺。

0083653GlazierDeveloping multicellular organisms exhibit dramatic changes in shape and form, as well as the emergence of rapidly changing spatial organization of specialized (differentiated) cell types, e.g. neurons and muscle fibers. These events, which generate the body plan and the various organs, depend on regulated gene expression, elaborate interactions between and among cells, and coordinated cell movement. Gene expression by itself cannot give a full account of the emergence of body plans, specific forms and shapes. Genetics and biochemistry interact with the physical properties of individual cells and cell aggregates in the course of development, making it a multiscale process of enormous complexity. As in many complex processes, however, one can discover dynamical and organizational rules at various levels if appropriate techniques are used to analyze developing organisms. This project brings together biologists, experimental and theoretical physicists, mathematicians, and computer scientists, each of whom has experience analyzing individual biophysical problems, and brings their expertise to bear on a specific developmental process-the formation of the vertebrate limb. Experimental and theoretical methods will be used to investigate the emergence of the limb bud from the body wall, the control of genes mediating cell aggregation, the spatiotemporal regulation of the limb skeletal pattern, and the ingrowth of nerve fibers into the limb from the spinal cord.This work will result in a multilevel characterization including subcellular, cellular and supracellular mechanisms which will provide a causal understanding of vertebrate limb development, as well as generate analytical tools that can be used to study similar problems in developmental biology. These tools will include software for solving the inevitably complex systems of mathematical equations that describe the interplay of genetic and material properties found in living embryos. New software will be built and distributed to model not only limb development, but also other types of organ formation and illness (e.g. tumor metastasis and vascularization). The overall strategy represents a step towards genuinely integrated research on animal development to deliver on the promise of the gene sequencing projects of the previous decade.