Molecular control of mechanical forces driving buckling morphogenesis of the small intestine

驱动小肠屈曲形态发生的机械力的分子控制

基本信息

批准号：
10521605
负责人：
Nandan L Nerurkar
金额：
$ 47.62万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521605
关键词：
3-Dimensional Abdomen Actomyosin Address Adolescence Area Automobile Driving Back Behavior Biological Biology Bioreactors Birth Cell Count Cell Proliferation Cell Size Cell Volumes Cells Cerebral cortex Chick Collecting Tube Congenital Abnormality Congenital Disorders Cues Dependence Development Embryo Embryonic Development Engineering Extracellular Matrix FRAP1 gene Feedback Genes Geometry Goals Growth Hand Intestinal Obstruction Intestinal Volvulus Intestines Length Light Link Measurement Measures Mechanics Mediating Mesentery Microbial Biofilms Midgut Molecular Morphogenesis Morphology Operative Surgical Procedures Organ Organism Organogenesis Pathway interactions Pattern Pharmacological Treatment Phenotype Physics Play Prevalence Process Regenerative Medicine Regulation Role Shapes Signal Pathway Signal Transduction Small Intestines Stereotyping Stress Stretching Study models Surface Testing Tissue Engineering Tissues Tube Vision Work body cavity cell behavior cell type design driving force experimental study follow-up insight mathematical model mechanical force mortality risk multidisciplinary physical process physical property repaired stereotypy

3-Dimensional Abdomen Actomyosin Address Adolescence Area Automobile Driving Back Behavior Biological Biology Bioreactors Birth Cell Count Cell Proliferation Cell Size Cell Volumes Cells Cerebral cortex Chick Collecting Tube Congenital Abnormality Congenital Disorders Cues Dependence Development Embryo Embryonic Development Engineering Extracellular Matrix FRAP1 gene Feedback Genes Geometry Goals Growth Hand Intestinal Obstruction Intestinal Volvulus Intestines Length Light Link Measurement Measures Mechanics Mediating Mesentery Microbial Biofilms Midgut Molecular Morphogenesis Morphology Operative Surgical Procedures Organ Organism Organogenesis Pathway interactions Pattern Pharmacological Treatment Phenotype Physics Play Prevalence Process Regenerative Medicine Regulation Role Shapes Signal Pathway Signal Transduction Small Intestines Stereotyping Stress Stretching Study models Surface Testing Tissue Engineering Tissues Tube Vision Work body cavity cell behavior cell type design driving force experimental study follow-up insight mathematical model mechanical force mortality risk multidisciplinary physical process physical property repaired stereotypy

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项目摘要

PROJECT SUMMARY/ABSTRACT The broad goal of this work is to understand how molecular cues orchestrate and interact with the physical forces to drive vertebrate morphogenesis. Specifically, we focus on looping of the small intestine, a process essential for packing of the lengthy intestine within the abdomen, that when defective leads to devastating congenital disorders. Loops arise due to buckling of the intestinal tube as it elongates against the constraint of its attached mesentery. The resulting loop wavelength and curvature can be predicted from a handful of experimentally measured physical properties, comprising tissue geometry, growth rate, and stiffness. Buckling has emerged as a core mechanism of shaping various tissues and organs in the embryo. However, the elegant simplicity of buckling mechanics often betrays the biological complexity that engenders and constrains this physical process. Indeed, an understanding of buckling morphogenesis that integrates physics with the underlying molecular cues and dynamic cell behaviors is lacking in most contexts. We recently identified BMP signaling as a key pathway controlling gut looping. With this pathway in hand, the present application exploits a well-developed understanding of the associated mechanics to study the molecular and cell biological control of buckling morphogenesis, as well as how forces generated during development feed back to modulate these controls. We begin by asking how BMP-dependent acto-myosin activity in the mesentery contributes to tissue mechanics through manipulation of extracellular matrix organization (Aim 1), focusing on the ability of this tissue to accommodate large strains (>100%) before stiffening; this behavior, known as constitutive nonlinearity, is a critical determinant of looping morphology, but its biological basis and morphological function are often overlooked in development. Next, we build upon the striking observation that BMP establishes differential growth by restricting mesentery elongation in a proliferation-independent manner (Aim 2), testing the hypothesis that BMP regulates cell size to set up differential growth, driving buckling. Therefore, Aims 1 and 2 focus on BMP-dependent mechanisms of elastic energy storage within the mesentery. This energy storage must be precisely balanced with energy dissipation to generate stereotyped looping. To address this, we examine the control of proliferative growth of the mesentery (Aim 3), focusing on the Hippo signaling pathway and how forces generated by differential growth may feedback on proliferation. These cross- disciplinary studies combine retroviral gene misexpression, analyses of cell behavior, force and stiffness measurements, tensile bioreactor studies, and mathematical modeling. The long term vision is to establish mechano-molecular rules or design principles of embryogenesis, enabling a true engineering approach to regenerative medicine, wherein stiffness, stress, and strain can be biologically programmed alongside cell type specification to instruct the assembly of functional three dimensional tissues and organs.

项目摘要/摘要这项工作的广泛目标是了解分子提示如何协调和与物理互动驱动脊椎动物形态发生的力。具体而言，我们专注于循环小肠，一个过程对于腹部内长肠的包装至关重要，当有缺陷导致毁灭性时先天性疾病。循环是由于肠管的屈曲而屈曲，因为它的肠系膜。可以从少数几个实验测量的物理特性，包括组织几何形状，生长速率和刚度。屈曲已成为塑造胚胎中各种组织和器官的核心机制。但是，优雅屈曲力学的简单性经常背叛产生和限制的生物学复杂性物理过程。确实，对屈曲形态发生的理解将物理学与在大多数情况下，都缺乏潜在的分子提示和动态细胞行为。我们最近确定了BMP 信号作为控制肠道循环的关键途径。借助此途径，本应用程序利用了对研究的相关力学的了解良好，以研究分子和细胞生物学控制屈曲形态发生，以及在发育过程中产生的力如何调节这些力控件。首先，我们询问肠系膜中依赖BMP的肌球蛋白活性如何有助于组织通过操纵细胞外基质组织的力学（AIM 1），重点是组织在加强之前可容纳大型菌株（> 100％）；这种行为，称为本构非线性，是循环形态的关键决定因素，但其生物学基础和形态学功能经常被忽视。接下来，我们基于BMP建立的惊人观察通过以非扩散方式限制肠系膜伸长来限制差异增长（AIM 2），测试 BMP调节细胞大小以建立差异生长，驱动屈曲的假设。因此，目标1 2关注肠系膜内弹性能量存储的BMP依赖性机制。这个能量必须精确地与能量耗散平衡存储，以产生定型的循环。为了解决这个问题我们检查了肠系膜增殖生长的控制（AIM 3），重点是河马信号传导途径以及差异增长产生的力如何反馈对增殖。这些交叉纪律研究结合了逆转录病毒基因的表现，细胞行为的分析，力和刚度测量，拉伸生物反应器研究和数学建模。长期视野是建立机械分子规则或胚胎发生的设计原则，使真正的工程方法再生医学，其中刚度，压力和应变可以与细胞类型一起进行生物编程指导组装功能性三维组织和器官的规范。