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.