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

• 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
• 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

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。