CELLULAR/MOLECULAR DETERMINANTS IN ORAL CARCINOGENESIS

该应用的长期目标是阐明细胞 以及转化生长因子-α（TGF- α）及其受体，表皮生长因子受体（EGFR），可以 影响人体口腔粘膜组织的恶变。 本次更新申请旨在扩展之前的研究结果 资助期详细说明 TGF-的细胞形式和生物活性 α由人类嗜酸性粒细胞和口腔角质形成细胞表达。 转化生长因子-α是 生长因子/细胞因子肽分子，可表示为 可溶和/或膜锚定形式。 本次融资期间 在此期间，我们的实验室做出了新的观察，即口腔癌- 相关的人类嗜酸性粒细胞可以表达 TGF-α，并且人类 恶性口腔角质形成细胞表达的 TGF-α 水平高于口腔恶性角质形成细胞 正常对应。 在此延续应用中，我们假设 浸润性嗜酸性粒细胞和恶性口腔角质形成细胞均表达 TGF-α 的可溶性形式以及膜锚定形式。 我们 进一步提出这两种细胞形式都具有生物活性， 正常人的TGF-α生物合成存在差异 与恶性人类口腔角质形成细胞相比。 我们将进行详细的 研究阐明生物合成、细胞形式以及 嗜酸性粒细胞表达的 TGF-α 的生物活性， 正常和恶性的人类口腔角质形成细胞。 因为正常的周边 血液嗜酸性粒细胞不表达 TGF-α，这是一组嗜酸性粒细胞特异性的 将检查细胞因子以确定其激活 TGF-的能力 这些粒细胞的α表达。 这些研究应该提供 关于嗜酸性粒细胞和恶性口腔癌如何发生的重要机制见解 角质形成细胞可影响人体口腔恶变 通过 TGF-α/EGFR 途径角质形成细胞。 拟议的工作基于 基于来自我们实验室的大量数据，并将采用 实验室中已经建立的实验方法 申请人。 因此，这项工作很有可能成功提供 阐明嗜酸性粒细胞潜在意义的新信息 和口腔角质形成细胞在 TGF-α 的产生中 人类口腔癌发生的微环境。

The long-term objective of this application is to elucidate the cellular and molecular mechanisms by which transforming growth factor-alpha (TGF- alpha) and its receptor, epidermal growth factor receptor (EGFR), can influence the malignant transformation of human oral mucosal tissues. This renewal application aims to extend the findings of the previous funding period to detail the cellular forms and bioactivity of the TGF- alpha expressed by human eosinophils and oral keratinocytes. TGF-alpha is a growth factor/cytokine-peptide molecule which can be expressed as soluble and/or membrane-anchored forms. During the current funding period, our laboratory has made the novel observations that oral cancer- associated human eosinophils can express TGF-alpha and that human malignant oral keratinocytes express higher levels of TGF-alpha than the normal counterpart. In this continuation application, we hypothesize that the infiltrating eosinophils and malignant oral keratinocytes express both the soluble as well as the membrane anchored forms of TGF-alpha. We further propose that both of these cellular forms are biologically active, and there are differences in the biosynthesis of TGF-alpha by the normal versus malignant human oral keratinocytes. We will perform detailed studies to elucidate the biosynthesis, cellula forms, as well as the biological activities of the TGF-alpha expressed by the eosinophils, normal and malignant human oral keratinocytes. Because normal peripheral blood eosinophils do not express TGF-alpha, a panel of eosinophil-specific cytokines will be examined to determine their ability to activate TGF- alpha expression by these granulocytes. These studies should provide important mechanistic insights into how eosinophils and malignant oral keratinocytes can influence the malignant transformation of human oral keratinocytes via the TGF-alpha/EGFR pathway. The proposed work is based on a body of data derived from our laboratory, and will employ experimental approaches already established in the laboratories of the applicants. Thus, the work has a high likelihood of success in providing new information to elucidate the potential significance of the eosinophil and oral keratinocyte in the production of TGF-alpha in the microenvironment of developing human oral cancer.