Elucidating Mechanisms of Mechanosensitivity During Secondary Chondrogenesis

阐明继发软骨形成过程中机械敏感性的机制

基本信息

批准号：
8829660
负责人：
Katherine Christine Woronowicz
金额：
$ 3.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829660
关键词：
Address Agonist Architecture Biological Models Biology Biomechanics Birds Blood Vessels Bone Surface Calcium Cartilage Cell Transplants Cells Chick Embryo Chickens Chimera organism Chondrocytes Chondrogenesis Congenital Abnormality Cues Data Development Disease Ducks Embryo Environment Epithelium Equilibrium Event FGFR2 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gated Ion Channel Goals Health Human Implant Individual Injury Ion Channel Jaw Joints Lead Life Lifting Link Maintenance Mandible Mechanics Mediating Mesenchymal Stem Cells Mesenchyme Molecular Morphogenesis Muscle Operative Surgical Procedures Paralysed Pathway interactions Patients Pattern Physical condensation Play Process Publishing Pulmonary Hypertension Quail Quality of life Regulation Role Seeds Series Signal Pathway Signal Transduction Skeleton Smooth Muscle Myocytes Staging Stretching Structure System Temporomandibular Joint Disorders Tendon structure Testing Tissues Trauma base bone cell motility cellular transduction feeding gain of function hatching inhibitor/antagonist loss of function novel programs regenerative therapy research study response skeletal skeletal tissue small molecule spatiotemporal transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): Through all stages of life, the skeleton is optimized for detecting and adapting to biomechanical forces. When the delicate balance that maintains skeletal health is disrupted by disease or injury, an individual's quality of life can deteriorate rapidly. The goal of this project is to identify mechanisms that allow the skeleton to sense and respond to mechanical forces. One skeletal tissue that is highly attuned to detecting mechanical force is secondary cartilage. Secondary cartilage initially develops on regions of bone in the jaw skeleton in response to forces arising during embryonic motility. In the absence of proper mechanical forces, secondary cartilage fails to form, and can also degenerate at any point as in temporomandibular disorders (TMD) and in patients with immobilized jaws. Though secondary cartilage is essential for jaw functionality, little is known about the molecular mechanisms that induce and maintain secondary cartilage. To address this issue, the current proposal employs an avian model system that exploits species-specific differences in the way secondary cartilage has evolved to support specialized modes of feeding. Duck feed by using their jaws to scoop and filter through wet sediment. Even before hatching, secondary cartilage arises in the duck mandibular adductor enthesis, which inserts laterally and thus greatly extends the coronoid process. This creates a robust interface between the tendon of the mandibular adductor muscle and the mandible, and transmits the powerful contractions necessary to lift the jaw. In contrast, chick feed primarily by pecking at seed, and their mandibular adductor muscle inserts dorsally along the coronoid process of the mandible without any secondary cartilage. These key distinctions are apparent in duck and chick embryos, even though there are no significant differences in embryonic jaw motility. This suggests that species-specific jaw architecture generates mechanical forces that are present in duck but not chick, leading to the differential activation of mechanosensitive signaling pathways during development. Based on published and preliminary data, we hypothesize that Fibroblast Growth Factor (FGF) and Calcium (Ca2+) signaling play a role in enabling the mandibular adductor enthesis to detect biomechanical forces and produce secondary cartilage. Aim 1 involves experiments that will determine whether FGF and Ca2+ signaling are necessary for secondary chondrogenesis. Beads soaked in small molecule inhibitors of FGF and Ca2+ signaling will be implanted beneath the epithelium overlying the presumptive duck coronoid process. Experiments in Aim 2 will uncover whether FGF and Ca2+ signaling are sufficient to promote secondary chondrogenesis by using FGF and Ca2+ signaling agonists in chick. Experiments of Aim 3 will employ chick-duck chimeras to determine whether chick cells are competent to form secondary cartilage when in a duck environment. Understanding mechanisms that regulate secondary chondrogenesis will lead to regenerative therapies for conditions involving loss of secondary cartilage such as TMD and those that occur following trauma.

描述（由申请人提供）：在生命的各个阶段，骨骼都经过优化以检测和适应生物力学力。当维持骨骼健康的微妙平衡因疾病或受伤而被破坏时，个人的生活质量可能会迅速恶化。该项目的目标是确定允许骨骼感知和响应机械力的机制。一种高度适应检测机械力的骨骼组织是次级软骨。次级软骨最初在颌骨骨骼区域发育，以响应胚胎运动过程中产生的力。在缺乏适当的机械力的情况下，次级软骨无法形成，并且还可能在任何时候退化，例如颞下颌疾病 (TMD) 和下颌固定的患者。尽管次级软骨对于下颌功能至关重要，但人们对诱导和维持次级软骨的分子机制知之甚少。为了解决这个问题，当前的提案采用了一种鸟类模型系统，该系统利用次生软骨进化方式的物种特异性差异来支持专门的喂养模式。鸭子通过用下巴铲起并过滤潮湿的沉积物来喂食。即使在孵化之前，鸭下颌内收肌附着点中也会产生次级软骨，该附着点横向插入，从而大大延长冠突。这在下颌内收肌腱和下颌骨之间形成了坚固的界面，并传递抬起下颌所需的强大收缩。相比之下，雏鸡主要通过啄食种子来进食，它们的下颌内收肌沿着下颌骨冠突向背侧插入，没有任何次级软骨。尽管胚胎下颌运动没有显着差异，但这些关键区别在鸭和鸡胚胎中很明显。这表明物种特异性的下颌结构会产生鸭子而非雏鸡中存在的机械力，从而导致发育过程中机械敏感信号通路的差异激活。根据已发表的初步数据，我们假设成纤维细胞生长因子 (FGF) 和钙 (Ca2+) 信号传导在使下颌内收肌附着点检测生物力学力并产生次级软骨方面发挥作用。目标 1 涉及的实验将确定 FGF 和 Ca2+ 信号传导是否是二次软骨形成所必需的。浸泡在 FGF 和 Ca2+ 信号小分子抑制剂中的珠子将被植入鸭冠突上皮的下方。目标 2 中的实验将揭示通过在鸡体内使用 FGF 和 Ca2+ 信号传导激动剂，FGF 和 Ca2+ 信号传导是否足以促进继发性软骨形成。目标 3 的实验将采用鸡鸭嵌合体来确定鸡细胞在鸭子环境中是否有能力形成次级软骨。了解调节继发软骨形成的机制将有助于对涉及继发软骨损失的疾病（如 TMD 和创伤后发生的疾病）进行再生治疗。