Spatial Dynamics of Tissue and Organ Size Control

组织和器官大小控制的空间动力学

• 批准号: 9150331
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 41.91万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150331
• 关键词: Ablation; Address; Affect; Animal Experimentation; Back; Bilateral; Biological; Biology; Cell Count; Cell Cycle; Cell Cycle Kinetics; Cell Lineage; Cell Size; Cells; Cerebral cortex; Cerebrum; Characteristics; Clinical; Congenital Abnormality; Cues; Data; Development; Dimensions; Engineering; Etiology; Feedback; Genes; Genetically Engineered Mouse; Goals; Growth; Human; Individual; Infection; Injury; Label; Learning; Length; Limb structure; Long-Term Effects; Malnutrition; Mathematics; Measurement; Measures; Mechanics; Methods; Microcephaly; Modeling; Molecular; Mus; Muscle; Neocortex; Nervous system structure; Neural Retina; Olfactory Epithelium; Organ; Organ Size; Pattern; Performance; Play; Probability; Process; Regulation; Resistance; Rest; Retina; Role; Signal Transduction; Specific qualifier value; Speed; Staging; Stem cells; Structure; System; Testing; Tissue Engineering; Tissues; Transgenic Mice; Variant; Work; base; cell killing; cell type; design; fascinate; feeding; human tissue; in vivo; insight; mathematical model; meetings; meter; models and simulation; organ growth; public health relevance; relating to nervous system; research study; spatiotemporal; stem; suicide gene; theories

 DESCRIPTION: The sizes of tissues and organs are specified with great precision, a fact we notice in the symmetry of bilateral structures (such as limbs), and the degree to which genetically identical individuals resemble each other. Not only do tissues and organs reach specific sizes, they do so in the face of cell killing or alterations to cell cycle kinetics, which suggests a feedback control mechanism. Work from our group on continually- renewing tissues has identified a general "integral negative feedback" strategy, whereby negative regulation of stem or progenitor cell renewal automatically achieves robust set-point control. Such feedback may be conveyed by diffusible growth factors-as we and others showed in the olfactory epithelium (OE), retina, and muscle-but a variety of molecules and mechanisms could act similarly. Regardless of mechanism, however, the ability of local feedback to control proliferation is subject to distance limitations: molecular and mechanical signals decay over characteristic length scales. The fact that such scales are often very short-on the order of 100 µm or less-raises questions about how local feedback could possibly control the sizes of tissues and organs that are three or four orders of magnitude larger. Here we address this issue through a combination of mathematical modeling and animal experimentation. Preliminary modeling has identified several strategies that could, in principle, enable large sizes to be controlled through short-range feedback. These strategies exploit the fact that controlling developmental tissue and organ growth is not a "steady-state" problem, but one of controlling a self-terminating trajectory. By considering a variety of possible cell lineage relationships and types of feedback interactions-all of which are motivated by observations in actual developing systems-we will use modeling and simulation to systematically discover the design principles out of which strategies for feedback control of large tissues and organs may be constructed. Subsequently, we will computationally test the hypothesis that the best way to distinguish experimentally among different potential growth-control strategies is by transiently ablating defined proportions of cells at specific lineage stages, and observing the consequences for final tissue size. Finally, we will perform just such transient cell ablations to investigate the development of three neural structures-the olfactory epithelium, the neural retina, and the cerebral neocortex-in mice, with the goal of identifying the strategies these tissues use for size control in different dimensions. This work will provide both basic insights into fundamental processes of development, and specific insights into size control in the nervous system. The results will be of direct relevance o the etiology of microcephaly and other birth defects, as well as to clinical phenomena of stunting, catch-up growth, and growth-asymmetry.

 描述：组织和器官的大小是非常精确的，我们在双侧结构（例如四肢）的对称性以及基因相同的个体彼此相似的程度中注意到这一事实。组织和器官不仅会达到特定的大小，而且还会面临细胞杀伤或细胞周期动力学的改变，这 提出了反馈控制机制。我们小组在持续更新组织方面的工作已经确定了一种通用的“整体负反馈”策略，通过干细胞或祖细胞更新的负调节自动实现稳健的设定点控制。这种反馈可能是通过扩散生长因子传递的——正如我们和其他人在嗅觉上皮（OE）、视网膜和肌肉中所显示的那样——但多种分子和机制也可以发挥类似的作用。然而，无论机制如何，局部反馈控制增殖的能力 受到距离限制：分子和机械信号在特征长度尺度上衰减。事实上，这种尺度通常非常短，约为 100 µm 或更小，这引发了局部反馈如何控制大三到四个数量级的组织和器官尺寸的问题。 在这里，我们通过数学建模和动物实验相结合来解决这个问题。初步建模已经确定了几种策略，原则上可以通过以下方式控制大尺寸： 短程反馈。这些策略利用了这样一个事实：控制发育组织和器官生长不是“稳态”问题，而是控制自我终止轨迹的问题。 通过考虑各种可能的细胞谱系关系和反馈相互作用的类型（所有这些都是由实际开发系统中的观察激发的），我们将使用建模和模拟来系统地发现可以构建大型组织和器官反馈控制策略的设计原则。随后，我们将通过计算测试以下假设：通过实验区分不同潜在生长控制策略的最佳方法是瞬时消融特定谱系阶段的特定比例的细胞，并观察对最终组织大小的影响。最后， 我们将进行这种瞬时细胞消融，以研究小鼠三种神经结构（嗅觉上皮、神经视网膜和大脑新皮质）的发育，目的是确定这些组织在不同维度上控制尺寸的策略。这项工作将提供对发育基本过程的基本见解，以及对神经系统大小控制的具体见解。结果将与小头畸形和其他出生缺陷的病因学以及发育迟缓、追赶性生长和生长不对称的临床现象直接相关。