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：
10671046
负责人：
Nandan L Nerurkar
金额：
$ 47.39万
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/10671046
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 Elasticity Embryo Embryonic Development Engineering Extracellular Matrix FRAP1 gene Feedback Genes Geometry Goals Growth Hand Intestinal Obstruction Intestinal Volvulus Intestines Length 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 Proliferating Regenerative Medicine Regulation Role Shapes Signal Pathway Signal Transduction Small Intestines Specific qualifier value Stereotyping Stress Stretching Study models Surface Testing Tissue Engineering Tissues Tube Work body cavity cell behavior cell type design driving force experimental study follow-up insight mathematical model mechanical drive mechanical force mortality risk multidisciplinary physical process physical property repaired stereotypy

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.

项目概要/摘要这项工作的总体目标是了解分子线索如何与物理信号协调并相互作用。驱动脊椎动物形态发生的力。具体来说，我们关注小肠的循环，这是一个过程对于将长肠包裹在腹部至关重要，如果有缺陷，就会导致毁灭性的后果先天性疾病。由于肠管在不受其附着的肠系膜。由此产生的环路波长和曲率可以从一些数据中预测出来实验测量的物理特性，包括组织几何形状、生长速率和硬度。屈曲已成为塑造胚胎中各种组织和器官的核心机制。然而，优雅的屈曲力学的简单性常常暴露了产生和限制这种现象的生物复杂性物理过程。事实上，对屈曲形态发生的理解将物理学与在大多数情况下，缺乏潜在的分子线索和动态细胞行为。我们最近确定了 BMP 信号传导是控制肠道循环的关键途径。有了这条途径，本申请利用了对相关力学的深入了解，以研究分子和细胞生物控制屈曲形态发生，以及发育过程中产生的力如何反馈以调节这些控制。我们首先询问肠系膜中 BMP 依赖性肌动球蛋白活性如何对组织产生影响通过操纵细胞外基质组织（目标 1）来研究力学，重点关注这种能力组织在硬化前适应大应变（>100%）；这种行为被称为本构性非线性，是循环形态的关键决定因素，但其生物学基础和形态功能开发过程中经常被忽视。接下来，我们以 BMP 建立的惊人观察为基础通过以不依赖增殖的方式限制肠系膜伸长来实现差异生长（目标 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 重点关注肠系膜内弹性能量储存的 BMP 依赖性机制。这种能量存储必须与能量耗散精确平衡，以产生定型循环。为了解决这个问题，我们检查肠系膜增殖生长的控制（目标 3），重点关注 Hippo 信号传导途径以及差异生长产生的力量如何反馈增殖。这些跨学科研究结合了逆转录病毒基因错误表达、细胞行为、力和刚度分析测量、拉伸生物反应器研究和数学建模。长期愿景是建立胚胎发生的机械分子规则或设计原则，使真正的工程方法成为可能再生医学，其中硬度、应力和应变可以与细胞类型一起进行生物编程指导功能性三维组织和器官组装的规范。