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: 9038609
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 44.38万
• 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/9038609
• 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; Growth Factor; 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：组织和器官的大小以非常精确的精度指定，我们在双侧结构（例如四肢）的对称性中注意到这一事实，以及一般相同的个体相似的程度。组织和器官不仅可以达到特定尺寸 建议一种反馈控制机制。我们小组对连续更新组织的工作已经确定了一种一般的“积分反馈”策略，从而负调控茎或祖细胞更新会自动实现强大的设定点控制。这种反馈可以通过可扩散的生长因子传达 - 我们和其他在嗅觉上皮（OE），视网膜和肌肉中所示的反馈，但各种分子和机制也可以类似。但是，无论机制如何，局部反馈控制增殖的能力 受距离限制的约束：特征长度尺度上的分子和机械信号衰减。这样的量表通常非常短，这一事实是关于局部反馈如何控制三个或四个数量级的组织和器官的大小，这一事实是100 µm或更少提出的问题。在这里，我们通过数学建模和动物实验的结合来解决这个问题。初步建模已经确定了几种策略，这些策略原则上可以使大小可以通过 短程反馈。这些策略探讨了控制发育组织和器官生长不是“稳态”问题，而是控制自终止轨迹的问题。 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 - 由实际开发系统中观察到的各种反馈相互作用我们将使用建模和仿真来系统地发现设计原理，从哪些策略中构建了对大型组织和器官的反馈控制策略。随后，我们将在计算上检验以下假设：在不同的潜在生长控制策略之间区分实验的最佳方法是在特定的谱系阶段瞬时消除细胞的定义比例，并观察最终组织大小的后果。最后， 我们将仅执行这种瞬态细胞消融，以研究三种神经元结构的发展 - 嗅觉上皮，神经元视网膜和大脑新皮层中的小鼠，其目的是识别这些技巧在不同维度中用于尺寸控制的策略。这项工作将提供对发展基本过程的基本见解，又可以提供对神经系统大小控制的特定见解。结果将是直接相关的小头畸形和其他先天缺陷的病因，以及发育迟缓，追赶生长和生长与对称性的临床现象。