Decoding the mechanical interactions between tissue layers sculpting organ shape

解码塑造器官形状的组织层之间的机械相互作用

基本信息

批准号：
10572921
负责人：
Noah Prentice Mitchell
金额：
$ 14.24万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10572921
关键词：
3-Dimensional Ablation Atlases Biological Models Biology Calcium Cell Shape Cells Communities Complex Congenital Abnormality Cytoskeleton Development Developmental Biology Doctor of Philosophy Drosophila genus Elasticity Endoderm Ensure Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Health Heart Heart Abnormalities Homeobox Genes Human Image Lasers Learning Left Light Link Maps Measures Mechanical Stress Mechanics Mediating Microscopy Midgut Modeling Molecular Biology Morbidity - disease rate Morphogenesis Muscle Organ Organ Model Pattern Phase Physics Physiologic pulse Postdoctoral Fellow Process Regulator Genes Research Resolution Role Shapes Signal Transduction Structure Techniques Testing Tissue imaging Tissues Training Translating Tube Visceral Visualization Work cell behavior clinical application computer framework computerized tools constriction driving behavior driving force gene conservation imaging modality in silico in vivo malformation mechanical force mortality mutant novel optogenetics physical model programs spatiotemporal

项目摘要

PROJECT SUMMARY/ABSTRACT Organ shape is vital for proper function. Malformations in the looping and folding of the heart, for instance, represent the leading cause of birth defect mortality in humans. Visceral organs rely on the coordinated activity of multiple laminar tissue layers to fold and coil into targeted shapes. While the community has learned much about the genetic signals governing cell fates during development, less is understood about the mechanical stresses and tissue dynamics that translate gene expression into the shapes of organs. This proposal aims to link hox gene expression to physical forces driving 3D multilayer organ shape change using the D. melanogaster midgut as a model system. The midgut begins as a tube of two concentric tissue layers that undergoes a sequence of constrictions to fold into chambers. Hox genes — conserved master regulators of patterning during development — have long been known to govern the ﬁnal shape of this organ, but the mechanical stresses and tissue dynamics translating hox expression into organ shape have remained elusive. We recently found that organ constrictions proceed through a mechanical program mediated by calcium pulses in the outer layer, under the control of hox genes. Advances in light-sheet microscopy now enable live visualization of the whole organ at sub-cellular resolution during development. Integrating these imaging methods with physics approaches provides the ability to follow cell dynamics across tissue layers throughout morphogenesis and quantitatively relate genetic patterning in the tissue to the tissue mechanics and dynamic cellular behaviors driving 3D shape change. The proposed work aims to ﬁrst (1) decode the relationship between the hox gene expression pattern to the downstream pattern of calcium pulses in the midgut. (2) Secondly, a physical model will relate calcium pulses to tissue-scale mechanical stress, using spatiotemporal maps of calcium activity to constrain an in silico model of the morphing tissue. Together, these aims will reveal how genetic patterning controls a mechanical process to sculpt complex shapes in a bilayer organ. (3) Finally, this proposal will address how the midgut model visceral organ coils into a chiral tube later during development. Recent discoveries of `cell intrinsic' chirality, in which cytoskeletal machinery breaks left-right symmetry, have proven to provide a major role in determining organ-scale chirality. The mechanical process by which cell chirality translates into 3D organ-scale shape change, however, remains largely unknown. By combining the in toto imaging toolkit and molecular biology approaches mastered during the K99 phase with my expertise in chiral mechanics from my PhD, this aim will link cellular chirality to the dynamics of organ-scale coiling. Together, these research aims and the training in biology, microscopy, and modeling during the K99 phase will ensure I am equipped to begin an independent research lab revealing the physical mechanisms harnessed by biology to sculpt complex shapes of visceral organs.

项目概要/摘要器官形状对于心脏的正常功能至关重要。例如，内脏器官是导致人类出生缺陷死亡的主要原因。多个层状组织层的协调活动，以折叠和卷曲成目标形状。人们对发育过程中控制细胞命运的遗传信号了解很多，但对以下方面了解较少将基因表达转化为器官形状的机械应力和组织动力学。该提案旨在将 hox 基因表达与驱动 3D 多层器官形状变化的物理力联系起来黑腹果蝇中肠作为模型系统。中肠开始时是由两个同心组织层组成的管子，经历一系列收缩折叠成腔室的 Hox 基因——发育过程中保守的模式调节因子——已经长期以来人们都知道控制该器官的最终形状，但机械应力和组织动力学我们最近发现，将 hox 表达转化为器官形状仍然难以捉摸。在 hox 的控制下，执行由外层钙脉冲介导的机械程序光片显微镜的进步现在可以实现整个器官的亚细胞实时可视化。将这些成像方法与物理方法相结合提供了能力。在整个形态发生过程中跟踪跨组织层的细胞动力学，并定量关联遗传组织中的图案根据组织力学和动态细胞行为驱动 3D 形状变化。拟议的工作旨在首先 (1) 解码 hox 基因表达模式之间的关系 (2) 其次，物理模型将钙联系起来脉冲到组织尺度的机械应力，使用钙活性的时空图来约束计算机这些目标将共同揭示遗传模式如何控制机械。在双层器官中雕刻复杂形状的过程 (3) 最后，该提案将解决中肠的问题。在发育后期将内脏器官模型卷入手性管中。“细胞内在”的最新发现。手性，即细胞骨架机制打破左右对称性，已被证明在确定器官尺度的手性细胞手性转化为 3D 器官尺度的机械过程。然而，通过结合整体成像工具包和分子，形状变化仍然很大程度上未知。我在 K99 阶段掌握了生物学方法，凭借我的博士学位在手性力学方面的专业知识，这目标是将细胞手性与器官尺度卷曲的动力学联系起来。这些研究目标以及 K99 期间生物学、显微镜学和建模方面的培训阶段将确保我有能力开始一个独立的研究实验室，揭示物理机制生物学利用它来塑造内脏器官的复杂形状。