Regulation of esophageal epithelial biology

描述（由申请人提供）： 食管鳞状上皮具有类似肠上皮的分隔区。然而，在食管上皮中，与协调从增殖的基底细胞到分化的基底上细胞的转换的基因的关系存在显著差异。最终，基底上细胞向外迁移到管腔，经历形态学、生物化学和遗传学变化，最终脱落细胞斯劳到管腔中。上皮不断更新。然而，鉴于细胞更新的快速性，食管上皮易受感染因子和酸反流的损伤，并且存在使上皮易于永生化和恶性转化的关键基因变化的风险。 该建议的中心假设是表皮生长因子受体（EGFR）的表达和活化，其在基底细胞区室中是重要的，是增殖所必需的，但由于胰岛素生长因子结合蛋白-3（IGFBP 3）的上调而不足以转化，胰岛素生长因子结合蛋白-3（IGFBP 3）发挥抗增殖作用并促进分化和衰老。EGFR和IGFBP 3之间的相互作用通过废除p53和p16/pRb途径来克服，以促进细胞的转化。这一假设将通过以下相关的具体目的来实现：（1）理解EGFR介导的IGFBP 3上调的分子基础，通过比较原代人食管细胞（EPC）和用EGFR逆转录病毒转导的EPC的基因阵列来鉴定。(2)阐明显性阴性或突变型p53如何通过下调IGFBP 3与EGFR协同作用。(3)为了了解p16/pRb通路的废除如何可能有助于表达EGFR和突变型p53的细胞的转化。总之，该提案中的创新方法将为食管上皮生物学的调节提供新的机制见解，并为理解关键疾病和癌症遗传学提供基础。 拟议的工作将通过精心设计的指导计划，教学课程，利用科学核心设施和机构支持来促进。这项研究将为独立研究者地位提供一个长期框架。

DESCRIPTION (provided by applicant): The esophageal squamous epithelium has compartments reminiscent of the intestinal epithelium. However, there are striking differences in relationship to the genes that orchestrate the switch from proliferating basal cells to differentiated suprabasal cells in the esophageal epithelium. Eventually, suprabasal cells migrate outward towards the lumen undergoing morphological, biochemical and genetic changes, culminating in desquamated cells that slough into the lumen. The epithelium is continuously renewed. However, given the rapidity of cell turnover, there is susceptibility of the esophageal epithelium to injury by infectious agents and acid reflux, and risk for changes in critical genes that render the epithelium prone to immortalization and malignant transformation. The central hypothesis of this proposal is that epidermal growth factor receptor (EGFR) expression and activation, which is important in the basal cell compartment, is necessary for proliferation but insufficient for transformation due to the upregulation of insulin growth factor binding protein-3 (IGFBP3), which exerts antipreliferative effects and promotes differentiation and senescence. The interplay between EGFR and IGFBP3 is overcome by the abrogation of the p53 and p16/pRb pathways to foster transformation of cells. This hypothesis will be pursued by the following interrelated Specific Aims: (1) To understand the molecular basis of EGFR mediated upregulation of IGFBP3, identified through a gene array comparing primary human esophageal cells (EPC) and EPC retro-virally transduced with EGFR. (2) To elucidate how dominant-negative or mutant p53 cooperates with EGFR through the downregulation of IGFBP3. (3) To understand how the abrogation of the p16/pRb pathway may contribute to transformation in cells that express EGFR and mutant p53. Taken together, the innovative approaches in this proposal will provide new mechanistic insights into the regulation of esophageal epithelial biology, and provide a foundation for understanding key diseases and cancer genetics. The proposed work will be fostered through a carefully designed mentored program, didactic courses, utilization of scientific core facilities, and institutional support. The research will provide a long-term framework for independent investigator status.