BIOCOMPLEXITY--Multiscale Simulation of Avian Limb Development

[00:83653]发育中的多细胞生物在形状和形态上表现出巨大的变化，并且出现了快速变化的特殊（分化）细胞类型的空间组织，例如神经元和肌肉纤维。这些事件产生身体计划和各种器官，依赖于受调节的基因表达、细胞之间的复杂相互作用和协调的细胞运动。基因表达本身并不能完全说明身体计划、特定形式和形状的出现。在发育过程中，遗传和生物化学与单个细胞和细胞聚集体的物理特性相互作用，使其成为一个极其复杂的多尺度过程。然而，正如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生物体，人们可以在各个层次上发现动态的和组织的规则。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单个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。将采用实验和理论相结合的方法来研究肢体从体壁萌发、介导细胞聚集的基因调控、肢体骨骼模式的时空调控以及神经纤维从脊髓向肢体内生长。这项工作将导致包括亚细胞、细胞和超细胞机制在内的多层次表征，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解决不可避免的复杂数学方程组的软件，这些数学方程组描述了在活胚胎中发现的遗传和物质特性的相互作用。新的软件将被建立和分发，不仅用来模拟肢体的发育，而且用来模拟其他类型的器官形成和疾病（如肿瘤转移和血管形成）。这一总体战略代表着朝着真正综合的动物发育研究迈出了一步，以实现前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.