GROWTH FACTORS AND GINGIVAL FIBROSIS

生长因子和牙龈纤维化

• 批准号: 7051437
• 负责人: PHILIP C TRACKMAN
• 金额: $ 26.22万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051437
• 关键词: apoptosis; biological signal transduction; biomarker; cell proliferation; clinical research; collagen; connective tissue; connective tissue growth factor; cyclic AMP; drug adverse effect; fibroblasts; fibroma; fibrosis; genetic transcription; gingiva disorder; growth factor; human subject; immunocytochemistry; monoclonal antibody; patient oriented research; phenytoin; prostaglandin receptor; prostaglandins; transforming growth factors

DESCRIPTION (provided by applicant): The clinical condition of gingival overgrowth consists of excess gingival tissues that creates disturbances in the oral environment and creates related systemic complications. For example, impaired mastication and impaired oral hygiene can result, respectively, in poor nutrition and increased microbial load in the oral cavity. There are two principal classifications of gingival overgrowth. Drug-induced gingival overgrowth is a side effect resulting from therapy with certain pharmacologic agents. Hereditary gingival fibromatosis is unrelated to pharmacological therapies. Recent studies from our laboratory show that phenytoin-induced gingival overgrowth lesions are fibrotic and contain elevated levels of connective tissue growth factor (CTGF), whereas nifedipine- and cyclosporin A-induced lesions are less fibrotic and have low levels of CTGF, and non-overgrowth tissues have no detectable CTGF. Our in vitro studies show that CTGF stimulates insoluble collagen accumulation in cultured human gingival fibroblasts. Fibrosis and CTGF levels have been associated in other pathologies. The molecular and cellular activities stimulated by CTGF that promote fibrosis are not well understood. The goals of the current proposal are (1) to identify functional domain(s) of CTGF that stimulate insoluble collagen accumulation, proliferation and apoptosis by cultured human gingival fibroblasts utilizing a series of domain-specific monoclonal CTGF antibodies; (2) determine mechanisms by which phenytoin increases CTGF itself in cultured human gingival fibroblasts focusing on prostaglandin and CAMP metabolism, and on phenytoin modulation of signal transduction pathways related to TGF-beta stimulated CTGF transcription (3) assay human drug-induced gingival overgrowth tissues and hereditary human gingival overgrowth tissues for the presence of markers related to the novel molecular mechanisms explored in vitro: prostaglandin receptors, proliferation markers, and markers for apoptosis. This experimental approach that utilizes bioassays of human gingival fibroblasts in vitro, and human gingival overgrowth tissues samples is expected to identify biologically active domains of CTGF, and mechanisms by which CTGF promotes gingival fibrosis. In addition, these findings will likely have relevance to fibrotic pathologies that occur in other tissues that also contain elevated levels of CTGF.

描述（由申请人提供）：牙龈过度生长的临床状况包括过量的牙龈组织，其在口腔环境中造成干扰并产生相关的全身并发症。例如，咀嚼受损和口腔卫生受损可分别导致口腔中营养不良和微生物负荷增加。牙龈增生有两种主要的分类。药物引起的牙龈增生是由某些药物治疗引起的副作用。遗传性牙龈纤维瘤病与药物治疗无关。我们实验室的最新研究表明，苯妥英诱导的牙龈增生病变是纤维化的，含有结缔组织生长因子（CTGF）水平升高，而硝苯地平和环孢素A诱导的病变纤维化程度较低，CTGF水平较低，非增生组织没有检测到CTGF。我们的体外研究表明，CTGF刺激培养的人牙龈成纤维细胞中不溶性胶原蛋白的积累。纤维化和CTGF水平与其他病理学相关。由CTGF刺激的促进纤维化的分子和细胞活性还不清楚。 本研究的目的是（1）利用一系列结构域特异性单克隆CTGF抗体，通过培养的人牙龈成纤维细胞，鉴定CTGF刺激不溶性胶原积累、增殖和凋亡的功能结构域;（2）确定苯妥英增加培养的人牙龈成纤维细胞中CTGF本身的机制，重点是前列腺素和cAMP代谢，和苯妥英调节与TGF-β刺激的CTGF转录相关的信号转导途径（3）测定人药物诱导的牙龈过度生长组织和遗传性人牙龈过度生长组织中与体外探索的新分子机制相关的标志物的存在：前列腺素受体、增殖标记物和凋亡标记物。该实验方法利用体外人牙龈成纤维细胞和人牙龈过度生长组织样品的生物测定，预计将鉴定CTGF的生物活性结构域，以及CTGF促进牙龈纤维化的机制。此外，这些发现可能与其他组织中也含有升高水平的CTGF的纤维化病理学有关。