Growth Factors and Gingival Fibrosis

生长因子和牙龈纤维化

• 批准号: 7475260
• 负责人: PHILIP C TRACKMAN
• 金额: $ 35.08万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475260
• 关键词: 3-Dimensional; Adverse effects; Affect; Biological Markers; Biological Process; Cells; Cellular biology; Class; Collagen; Condition; Connective Tissue; Cyclosporine; Data; Deposition; Development; Dinoprostone; Down-Regulation; Environment; Enzymes; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Regulation; Genes; Genetic; Gingiva; Gingival Fibromatosis; Gingival Overgrowth; Growth Factor; Hepatocyte Growth Factor; Human; Immunohistochemistry; In Situ; In Vitro; Individual; Inherited; Integrin alpha6beta1; Integrins; Invaded; Kidney; Laboratories; Lead; Lesion; Mastication; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mesenchymal; Modeling; Molecular; Molecular Target; Morphology; Nifedipine; Oral; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenytoin; Play; Principal Investigator; Process; Production; Publishing; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Therapeutic; Tissues; Work; collagenase 3; connective tissue growth factor; epithelial to mesenchymal transition; extracellular; in vivo; inhibitor/antagonist; insight; monolayer; novel; novel therapeutics; oral tissue

DESCRIPTION (provided by applicant): Gingival overgrowth is a side effect of specific medications, and occurs as inherited and idiopathic forms (HGF). The condition impairs mastication, and predisposes affected individuals to systemic complications. Although gingival overgrowth lesions appear clinically similar, our studies have shown that the molecular and cellular features of gingival overgrowth vary as a function of the cause. Phenytoin-induced gingival overgrowth and HGF lesions are highly fibrotic and contain high levels of connective tissue growth factor (CTGF); whereas cyclosporin A induced overgrowth is less fibrotic, and contains low amounts of CTGF; and nifedipine-induced gingival overgrowth is intermediated in all respects. Recent studies have identified tissue specific pathways that provide the mechanism for elevated CTGF expression in fibrotic gingival tissues, and potential therapeutic strategies. In addition, we have published evidence that CTGF promotes extracellular matrix deposition via alpha-6 and beta-1 integrins. Preliminary data suggest that the process of epithelial- mesenchymal transition (EMT) contributes to all forms of gingival overgrowth; and that a critically important matrix metalloproteinase (MMP-13) is down regulated in fibrotic forms of gingival overgrowth. Thus, two aims are proposed. In Aim 1 we will establish that EMT occurs in all forms of human gingival overgrowth in vivo, and we will evaluate the mechanism of inhibitors of EMT to block progression of abnormalities in in vitro studies of primary gingival epithelial cells and fibroblasts. Aim 2 proposes to evaluate the hypothesis that CTGF regulates extracellular collagen processing enzymes and a matrix metalloproteinase (MMP-13), thereby increasing net extracellular matrix accumulation. Proposed studies will determine CTGF stimulated signal transduction pathways and regulated downstream genes that lead to increased extracellular matrix deposition. These studies take advantage of a peptide that inhibits CTGF-dependent extracellular matrix deposition that we have recently identified. The proposed experimental approach utilizes in situ analyses of human gingival overgrowth tissues, and primary cultured human gingival epithelial cells grown in monolayer and three dimensional configurations. Studies will identify novel cellular and molecular pathways that contribute to gingival overgrowth. Findings will have relevance to fibrosis in both oral and non-oral tissues in which CTGF is a contributing factor, thus potentially identifying new therapeutic strategies in various tissues.

描述（由申请人提供）：牙龈过度生长是特定药物的副作用，以遗传性和特发性形式（HGF）发生。这种情况会损害咀嚼功能，并使受影响的个体容易出现全身并发症。尽管牙龈过度生长病变在临床上看起来相似，但我们的研究表明，牙龈过度生长的分子和细胞特征因病因而异。苯妥英引起的牙龈过度生长和 HGF 病变高度纤维化，并含有高水平的结缔组织生长因子 (CTGF)；而环孢菌素 A 诱导的过度生长纤维化程度较低，并且含有少量的 CTGF；硝苯地平引起的牙龈过度生长在各个方面都有调节作用。最近的研究已经确定了组织特异性途径，这些途径提供了纤维化牙龈组织中 CTGF 表达升高的机制，以及潜在的治疗策略。此外，我们还发表了证据表明 CTGF 通过 alpha-6 和 beta-1 整合素促进细胞外基质沉积。初步数据表明，上皮-间质转化（EMT）过程会导致所有形式的牙龈过度生长。一种极其重要的基质金属蛋白酶（MMP-13）在牙龈过度生长的纤维化形式中下调。因此，提出了两个目标。在目标 1 中，我们将确定 EMT 发生在体内所有形式的人类牙龈过度生长中，并且我们将在原代牙龈上皮细胞和成纤维细胞的体外研究中评估 EMT 抑制剂阻止异常进展的机制。目标 2 提议评估以下假设：CTGF 调节细胞外胶原蛋白加工酶和基质金属蛋白酶 (MMP-13)，从而增加细胞外基质净积累。拟议的研究将确定 CTGF 刺激的信号转导途径和调节导致细胞外基质沉积增加的下游基因。这些研究利用了我们最近发现的一种抑制 CTGF 依赖性细胞外基质沉积的肽。所提出的实验方法利用对人类牙龈过度生长组织和以单层和三维结构生长的原代培养人类牙龈上皮细胞的原位分析。研究将确定导致牙龈过度生长的新细胞和分子途径。研究结果将与口腔和非口腔组织的纤维化相关，CTGF 是其中的一个促成因素，从而有可能确定各种组织的新治疗策略。