Regulation of PTHrP in Squamous Cell Carcinoma by the EGF Receptor

描述(由申请人提供)： Gwendoline Lorch D.V.M.，M.S.通过研究激素和生长因子及其在鳞状细胞癌(SCC)的发展和病理生物学中的作用，寻求成为一名独立的科学家，以支持在学术界和生物医学研究的事业。格温德伦·洛奇博士是美国兽医皮肤病学会(2001年)颁发的董事会证书。洛奇博士目前是俄亥俄州立大学兽医生物科学系的NRSA博士后研究员和博士生。博士毕业后，洛奇博士将被任命为兽医生物科学系的研究助理教授。她的研究目标是研究导致肺鳞状细胞癌中信号转导受扰、甲状旁腺激素相关蛋白(PTHrP)表达增加和体液恶性高钙血症(HHM)的表皮生长因子受体(EGFR)激酶信号转导。该项目将具有直接的临床应用，因为识别去调控的致癌蛋白酪氨酸激酶(PTK)导致PTHrP过表达将有助于识别有效和特异的PTK抑制剂。 PTHrP最初被认为是引起HHM的因素，并由所有鳞状细胞癌产生。PTHrP除了作为旁分泌和内分泌激素外，还调节细胞的分裂、分化和凋亡，在癌症和正常生物学中具有重要的作用。来自洛奇博士研究的重要新数据显示，EGFR信号诱导肺鳞状细胞癌中PTHrP的表达。有待检验的总体假设是，EGF配体与EGFR以自分泌方式共同作用，调节肺SCC中PTHrP的表达，并诱导HHM的发生。目的1研究表皮生长因子受体(EGFR)信号对体外培养的人鳞状细胞癌PTHrP基因表达及mRNA稳定性的影响。目的2利用异种移植模型和肺鳞状细胞癌细胞株，评价EGFR特异性酪氨酸激酶抑制剂对PTHrP mRNA表达、蛋白分泌和HHM发展的影响。目的3将通过检测治疗和对照高钙小鼠肺鳞状细胞癌模型中表达的基因，确定EGFR下游在调节PTHrP和诱导HHM中重要的分子靶点。这个项目已经完成了大量的初步数据。 兽医生物科学系是俄亥俄州立大学六所健康科学学院中一个成功的学术部门，拥有30名外部资助的内分泌学、分子生物学、实验病理学、肿瘤学和其他学科的研究人员。Thomas Rosol博士(赞助商)和John Foley博士(共同赞助商)的实验室为培养洛奇博士成为独立科学家所需的技能提供了极好的环境。 这项拟议的研究将使用创新的方法来研究细胞表面受体EGFR。这种受体以不成比例的数量存在，并在许多癌症中异常激活，导致细胞快速不受控制的生长。此外，这项建议旨在确定EGFR如何调节肺癌中过量的PTHrP产生，并导致危及生命的钙水平升高。我们试图确定导致PTHrP过量的特定细胞信号蛋白，这些蛋白可能是抗癌药物设计的候选靶点，并最终限制癌细胞的生存、生长和扩散。这项研究的结果将被转化为提高全球人类和动物癌症护理的标准。

DESCRIPTION (provided by applicant): Gwendolen Lorch D.V.M., M.S., seeks to become an independent scientist by studying hormone and growth factors and their role in the development and pathobiology of squamous cell carcinoma (SCC) in order to support a career in academia and biomedical research. Dr. Gwendolen Lorch is board-certified by The American College of Veterinary Dermatology (2001). Dr. Lorch is currently a NRSA postdoctoral fellow and Ph.D. student in the Department of Veterinary Biosciences at The Ohio State University. After completion of the Ph.D., Dr. Lorch will be appointed as research assistant professor in the Department of Veterinary Biosciences. Her research goal is to investigate epidermal growth factor receptor (EGFR) kinase signaling that leads to perturbed signal transduction and increased parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcemia of malignancy (HHM) in SCC of the lung. This project will have direct clinical application since the identification of deregulated oncogenic protein tyrosine kinases (PTK) leading to PTHrP overexpression will facilitate identification of potent and specific PTK inhibitors. PTHrP was initially identified as the factor responsible for HHM and is produced by all SCC. PTHrP has an important role in cancer and normal biology since it regulates cell division, differentiation, and apoptosis in addition to its function as a paracrine and endocrine hormone. Important new data from Dr. Lorch's research have revealed that EGFR signaling induces PTHrP expression in lung SCC. The overall hypothesis to be tested is that EGF ligands act in an autocrine manner with the EGFR to regulate PTHrP expression in lung SCC and induce the development of HHM. Aim 1 will measure the effects of EGFR signaling on PTHrP gene expression and mRNA stability in human SCC lines in vitro. Aim 2 will evaluate the use of EGFR-specific tyrosine kinase inhibitors on PTHrP mRNA expression, protein secretion, and development of HHM using xenograft models and lung SCC cell lines. Aim 3 will identify molecular targets downstream of the EGFR important in regulation of PTHrP and induction of HHM by measuring expressed genes in both treated and control hypercalcemic mouse models of lung SCC. Extensive preliminary data has been completed for this project. The Department of Veterinary Biosciences is a successful academic department among the six OSU Health Sciences Colleges with 30 extramurally funded researchers in endocrinology, molecular biology, experimental pathobiology, oncology, and other disciplines. The laboratories of Thomas Rosol, D.V.M., Ph.D. (sponsor) and John Foley, Ph.D. (co-sponsor) provide an excellent environment for developing the necessary skills for Dr. Lorch to become an independent scientist. The proposed research will use innovative approaches to investigate the cell surface receptor, EGFR. This receptor is present in disproportionate amounts and has abnormal activation in many cancers leading to rapid uncontrolled growth of the cells. Further, this proposal aims to identify how EGFR regulates excessive PTHrP production in lung cancer and causes life-threatening elevated calcium levels. We seek to identify specific cell signaling proteins that contribute to excessive PTHrP which may be candidate targets for design of anticancer drugs and would ultimately limit cancer cell survival, growth, and spread. The results of the research will then be translated to advance the standard of human and animal cancer care worldwide.