Linking cell forces to organ-scale morphogenesis of the small intestine

将细胞力与小肠器官尺度的形态发生联系起来

• 批准号: 10320734
• 负责人: John Francis Durel
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2024-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320734
• 关键词: Abdomen; Academia; Actomyosin; Adult; Advisory Committees; Area; Attention; Behavior; Biological; Biological Process; Biomedical Engineering; Biophysics; Birds; Birth; Cells; Chick; Communication; Congenital Abnormality; Contracts; Data; Dependence; Development; Developmental Biology; Diagnosis; Disease; Embryology; Embryonic Development; Engineering; Etiology; Extracellular Matrix; Geometry; Growth; Immunochemistry; Intestinal Volvulus; Intestines; Length; Light; Link; Mammals; Measurement; Mechanics; Mentorship; Mesentery; Midgut; Molecular; Molecular Biology; Morphogenesis; Morphology; Nutrient; Obstruction; Operative Surgical Procedures; Oral; Organ; Pharmacology; Physiological; Process; Professional Competence; Property; Regulation; Research; Signaling Protein; Small Intestines; Stereotyping; Stretching; Structure; Surface; Techniques; Testing; Tissues; Training; Translating; Tube; Work; antagonist; base; body cavity; bone morphogenic protein; cell behavior; congenital gastrointestinal disorder; gastrointestinal; improved; insight; mechanical force; nutrient absorption; regenerative; response; responsible research conduct; soft tissue; symposium

PROJECT SUMMARY / ABSTRACT The lengthy small intestine is organized into compact loops within the confines of the body cavity in order to achieve sufficient nutrient-absorbing surface area. Abnormal looping results in congenital gastrointestinal disorders, such as midgut volvulus, which are often debilitating or lethal. During development, these loops form by buckling, a common morphogenetic mechanism by which a tissue bends outward in response to compressive mechanical forces. Elongation of the initially straight gut tube against the constraint of its attached membranous mesentery results in compressive forces that buckle the tube into stereotyped loops. Loop morphology can be predicted from experimental measurement of a handful of physical parameters, including mesentery stiffness. In response to increasing stretch by the elongating gut tube, the mesentery is initially compliant before stiffening and resisting further extension, thereby forcing the tube to buckle. This dependence of stiffness on stretch is known as constitutive nonlinearity, a property well characterized in adult tissues but largely overlooked in development, where its biological determinants are poorly understood. Here, we propose to elucidate key biological bases of mesentery constitutive nonlinearity during small intestine looping. Preliminary data collected by the applicant strongly implicates cell contractility in tuning the stiffening transition of chick mesentery, with disruption of contractility surprisingly resulting in diminished mesentery compliance prior to unchanged stiffening. Together with prior work showing similar changes upon inhibition of bone morphogenic protein (BMP) activity, we hypothesize that BMP signaling induces cell contractility to tune mesentery pre-stiffening compliance (Aim 1) and that extracellular matrix (ECM) compaction by these contracting cells sets the stiffening transition (Aim 2). Experimental examination of this hypothesis will shed light on the mechanics of proper intestinal development by integrating molecular control of cell behavior and matrix organization with organ-scale looping, which will yield important insight into the etiology of gastrointestinal birth defects arising from improper looping. In completing these Aims, the applicant will receive training in experimental techniques spanning developmental biology and bioengineering, including chick embryology, molecular biology, immunochemistry, and soft tissue mechanics. The applicant will participate in cross-department seminars, attend and present at engineering and development conferences, and receive mentorship from the sponsor, co-sponsor, and advisory committee, who contribute a diverse range of expertise. The applicant will also train in responsible conduct of research, oral and written communication, mentorship, and many other career skills. This training will prepare the applicant for postdoctoral research in academia studying the origins of physiological disorders for regenerative applications.

项目摘要 /摘要 冗长的小肠被组织成紧凑的环形环，以便为了 达到足够的营养吸收表面积。异常循环导致先天性胃肠道 疾病，例如Midgut volvulus，通常使人衰弱或致命。在开发过程中，这些循环形式 通过屈曲，这是一种常见的形态发生机制 机械力。最初的直肠管的伸长延伸抵制其附着的膜的约束 肠系膜导致压缩力将管子扣成刻板的环。循环形态可以是 通过实验测量的少数物理参数（包括肠系膜刚度）进行了预测。在 通过伸长的肠管对增加拉伸的响应，肠系膜最初是顺从的 并抵抗进一步的延伸，从而迫使管子扣紧。刚度对拉伸的这种依赖性是 被称为构成性非线性，在成人组织中具有很好的特征，但在很大程度上被忽略了 开发，其生物决定因素的理解不足。在这里，我们建议阐明密钥 小肠循环过程中肠系膜本质非线性的生物基础。收集的初步数据 申请人强烈暗示细胞收缩性在调整雏鸡肠系膜的僵硬过渡时， 收缩性的破坏令人惊讶地导致肠系膜依从性降低，然后再加强。 与先前的工作一起显示出抑制骨形态发生蛋白（BMP）活性的类似变化， 我们假设BMP信号传导诱导细胞收缩性调整肠系膜前静止依从性（AIM 1） 这些收缩细胞的细胞外基质（ECM）压实设定了僵硬的过渡（AIM 2）。 该假设的实验检查将阐明适当肠发展的机制 通过将细胞行为的分子控制和基质组织与器官尺度循环整合在一起，这将产生 对循环不当引起的胃肠道出生缺陷的病因的重要洞察力。 在完成这些目标时，申请人将接受跨越发展的实验技术培训 生物学和生物工程，包括雏鸡胚胎学，分子生物学，免疫化学和软组织 力学。申请人将参加跨部门研讨会，参加Engineering和 开发会议，并获得赞助商，共同赞助者和咨询委员会的指导，他 贡献各种专业知识。申请人还将培训负责任的研究，口头和 书面交流，指导和许多其他职业技能。该培训将为申请人做好准备 学术界的博士后研究研究了用于再生应用生理障碍的起源。