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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.

项目总结/摘要器官的形状对正常的功能至关重要。心脏循环和折叠畸形，例如，是人类出生缺陷死亡的主要原因。内脏器官依赖于多个层状组织层的协调活动以折叠和盘绕成目标形状。而社区已经了解了很多关于发育过程中控制细胞命运的遗传信号，但对将基因表达转化为器官形状的机械应力和组织动力学。这一项提案旨在将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，地方黑腹中肠作为模型系统。中肠开始时是一个由两层同心组织层组成的管状结构，折叠成腔室。Hox基因--发育过程中模式化的保守主调节因子-- 长期以来，人们一直知道它控制着这个器官的最终形状，但机械应力和组织动力学将HOX表达转化为器官形状仍然是难以捉摸的。我们最近发现器官收缩在HOX的控制下，通过由外层中的钙脉冲介导的机械程序进行基因.光片显微镜的进步现在可以在亚细胞水平上实时观察整个器官。发展过程中的决议。将这些成像方法与物理方法相结合，在整个形态发生过程中跟踪组织层的细胞动力学，组织中的图案化到组织力学和驱动3D形状变化的动态细胞行为。这项工作的目的是首先（1）解码hox基因表达模式与中肠中钙脉冲的下游模式。(2)其次，物理模型将钙脉冲到组织规模的机械应力，使用钙活动的时空图来限制计算机模拟变形组织的模型。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塑造复杂形状的过程。(3)最后，本提案将讨论中肠如何在发育后期将内脏器官线圈建模为手性管。“细胞内在”的最新发现手性，其中细胞骨架机制打破左右对称，已被证明在决定器官尺度的手性。细胞手性转化为3D器官尺度的机械过程然而，形状变化在很大程度上仍然是未知的。通过结合全成像工具包和分子生物学方法掌握在K99阶段与我的专业知识手性力学从我的博士学位，这 aim将把细胞手性与器官尺度卷曲的动力学联系起来。总之，这些研究目标和K99期间的生物学，显微镜和建模培训这一阶段将确保我有能力开始一个独立的研究实验室，揭示物理机制被生物学利用来塑造复杂的内脏器官形状。