Growth Factor/Extracellular Matrix Interactions During Branching Morphogenesis

分支形态发生过程中生长因子/细胞外基质的相互作用

基本信息

批准号：
8743747
负责人：
Matthew Hoffman
金额：
$ 89.47万
依托单位：
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8743747
关键词：
Adult Affect Antithrombins Axon Binding Blood Vessels Cell surface Charge Communication Cues Defect Development Duct (organ) structure Engineering Enzymes Epithelial Epithelium Excision Extracellular Matrix FGF10 gene Fibroblast Growth Factor Ganglia Genetic Gland Glycoproteins Goals Growth Factor Head and Neck Neoplasms Heparitin Sulfate Human Inorganic Sulfates Lacrimal gland structure Morphogenesis Morphology Natural regeneration Nerve Neural Crest Neurons Oral health Organ Organogenesis Patients Pattern Peripheral Nervous System Production Quality of life RNA Interference Radiation Reporting Repression Role Salivary Salivary Glands Signal Transduction Simplexvirus Sjogren&apos s Syndrome Stem cells Structure of parasympathetic ganglion Submandibular gland Syndrome Therapeutic Unspecified or Sulfate Ion Sulfates cell type density digital fibroblast growth factor receptor 2b gland development insight nerve supply repaired sulfation sulfotransferase tumor

项目摘要

We are investigating how heparan sulfate influences FGFR2b signaling in specific progenitor cell types in the epithelium. A controversy remains in the HS field as to whether HS function requires specific patterns of sulfation or simply charge density. The reported function of 3-O-sulfated HS is to bind to antithrombin and the herpes simplex virus glycoprotein, gD1. We analyzed the expression of sulfotransferase enzymes in the SMG. We found that Hs3st-modified HS was present on the SMG epithelium and that RNAi knockdown of Hs3st reduces morphogenesis and proliferation. We are investigating how FGFR2b signaling controls HS production on the cell surface of epithelial end bud progenitor cells. We are also identifying the signals that initiate the innervation of the salivary gland. Nerves often follow alongside blood vessels to navigate to their targets using similar sets of guidance cues. However, defining the signals that initiate the association between the peripheral nervous system and the salivary epithelium will be important to regenerate or engineer functioning organs. During submandibular gland (SMG) organogenesis innervation begins when neural crest-derived neurons condense around the epithelial duct to form ganglia, which subsequently extend axons to innervate the epithelium of the gland. We are studying epithelial-derived factors that initiate the neuronal-epithelial communication resulting in neurons condensing around the duct. These epithelial signals are dependent on the localized repression of FGF signaling within the duct. In contrast, enhanced epithelial FGF signaling antagonizes these factors, resulting in defects in epithelial-neuronal communication leading to disrupted ganglia formation and epithelial morphology. This also results in a subsequent depletion of the epithelial progenitor cell reservoir. Our studies demonstrate that epithelial-derived factors are required for gangliogenesis and association with the epithelial duct. Signals that promote gangliogenesis and neuronal-epithelial interactions may inform organ engineering, regeneration, and repair.

我们正在研究上皮细胞中特定祖细胞类型中硫酸盐如何影响FGFR2B信号传导。关于HS功能是否需要特定的硫酸模式还是简单的电荷密度，HS领域仍然存在争议。 3-O硫化HS的报告功能是与抗凝血酶和单纯疱疹病毒糖蛋白GD1结合。我们分析了SMG中硫代转移酶的表达。我们发现，HS3ST修饰的HS存在于SMG上皮上，而HS3ST的RNAi敲低会降低形态发生和增殖。我们正在研究FGFR2B信号如何控制上皮末端芽祖细胞细胞表面上的HS产生。我们还确定了启动唾液腺神经支配的信号。神经经常与血管一起使用，使用类似的指导提示导航到目标。但是，定义启动周围神经系统与唾液上皮之间关联的信号对于再生或工程师功能器官非常重要。在下颌下腺（SMG）的过程中，当神经rest衍生的神经元围绕上皮管凝结以形成神经节时，神经支配始于形成神经节，随后将轴突延伸以支配腺体的上皮。我们正在研究启动神经元上皮通信的上皮因素，导致神经元在管道周围凝结。这些上皮信号取决于管道内FGF信号的局部抑制。相反，增强的上皮FGF信号传导拮抗了这些因素，从而导致上皮 - 神经元通信的缺陷导致神经节形成和上皮形态破坏。这也导致上皮祖细胞储层的随后耗竭。我们的研究表明，上皮衍生的因素是神经节生成和与上皮管的关联所必需的。促进神经节发生和神经元相互作用的信号可能会为器官工程，再生和修复提供信息。