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: 10157278
• 负责人: John Francis Durel
• 金额: $ 4.6万
• 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/10157278
• 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; Extracellular Structure; Geometry; Growth; Immunochemistry; Intestinal Volvulus; Intestines; Length; Light; Link; Mammals; Measurement; Mechanics; Mentorship; Mesentery; Midgut; Molecular; Molecular Biology; Molecular Structure; 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; 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.

项目概要/摘要 长长的小肠在体腔内组织成紧凑的环，以便 获得足够的养分吸收表面积。异常循环导致先天性胃肠道 疾病，例如中肠扭转，通常使人衰弱或致命。在开发过程中，这些循环形成 通过屈曲，这是一种常见的形态发生机制，组织通过这种机制响应压缩而向外弯曲 机械力。最初的直肠管相对于其附着的膜的约束而伸长 肠系膜产生压缩力，使管子弯曲成定型的环。循环形态可以是 通过对一些物理参数（包括肠系膜硬度）的实验测量来预测。在 为了响应拉长肠管增加的拉伸，肠系膜在变硬之前最初是顺应的 并阻止进一步延伸，从而迫使管子弯曲。刚度对拉伸的依赖性是 称为本构非线性，这是一种在成人组织中得到充分表征的特性，但在 发展，但对其生物决定因素知之甚少。在此，我们建议阐明关键 小肠循环过程中肠系膜本构非线性的生物学基础。收集的初步数据 申请人的研究强烈暗示了细胞收缩性在调节鸡肠系膜的硬化转变中， 令人惊讶的是，收缩性的破坏导致肠系膜顺应性在硬化不变之前降低。 与之前的研究一起显示，抑制骨形态发生蛋白（BMP）活性后会发生类似的变化， 我们假设 BMP 信号传导诱导细胞收缩性来调节肠系膜预硬化顺应性（目标 1） 这些收缩细胞对细胞外基质 (ECM) 的压实设定了硬化过渡（目标 2）。 对这一假设的实验检验将揭示肠道正常发育的机制 通过将细胞行为和基质组织的分子控制与器官规模的循环相结合，这将产生 对因不当循环引起的胃肠道出生缺陷的病因学有重要见解。 在完成这些目标的过程中，申请人将接受涵盖发育的实验技术的培训 生物学和生物工程，包括鸡胚胎学、分子生物学、免疫化学和软组织 机械师。申请人将参加跨部门研讨会、出席并出席工程和会议 发展会议，并接受赞助商、共同赞助商和咨询委员会的指导，他们 贡献多样化的专业知识。申请人还将接受负责任的研究、口头和 书面沟通、指导和许多其他职业技能。该培训将使申请人做好准备 学术界的博士后研究，研究再生应用的生理疾病的起源。