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Growth Factors and Gingival Fibrosis

生长因子和牙龈纤维化

基本信息

批准号：
8075548
负责人：
PHILIP C TRACKMAN
金额：
$ 33.68万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-04-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8075548
关键词：
3-Dimensional Adverse effects Affect Biological Process Cell Culture Techniques Cells Cellular biology Collagen 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 molecular marker monolayer novel novel therapeutics oral tissue

项目摘要

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，并以遗传和特发性形式（HGF）发生。这种情况会损害咀嚼功能，并使受影响的个体易患全身性并发症。虽然牙龈增生病变出现临床相似，我们的研究表明，牙龈增生的分子和细胞功能的原因不同。苯妥英诱导的牙龈过度生长和HGF病变是高度纤维化的，并含有高水平的结缔组织生长因子（CTGF）;而环孢菌素A诱导的过度生长是纤维化较少，并含有少量的CTGF;硝苯地平诱导的牙龈过度生长是在所有方面的中介。最近的研究已经确定了组织特异性途径，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，我们已经发表了CTGF通过α-6和β-1整合素促进细胞外基质沉积的证据。初步数据表明，上皮-间充质转化（EMT）的过程有助于所有形式的牙龈过度生长;并且一种至关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。在目的1中，我们将建立EMT发生在所有形式的人体牙龈过度生长在体内，我们将评估EMT的抑制剂的机制，以阻止在体外研究的原代牙龈上皮细胞和成纤维细胞的异常进展。目的2提出评估CTGF调节细胞外胶原加工酶和基质金属蛋白酶（MMP-13），从而增加净细胞外基质积累的假设。拟议的研究将确定CTGF刺激的信号转导途径和调节下游基因，导致细胞外基质沉积增加。这些研究利用了我们最近发现的抑制CTGF依赖性细胞外基质沉积的肽。所提出的实验方法利用原位分析的人牙龈增生组织，和原代培养的人牙龈上皮细胞生长在单层和三维配置。研究将确定新的细胞和分子途径，有助于牙龈过度生长。研究结果将与口腔和非口腔组织中的纤维化相关，其中CTGF是一个促成因素，从而可能在各种组织中确定新的治疗策略。