Regulation of PTHrP in Squamous Cell Carcinoma by the EGF Receptor

EGF 受体对鳞状细胞癌中 PTHrP 的调节

• 批准号: 7632055
• 负责人: Gwendolen Lorch
• 金额: $ 12.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632055
• 关键词: Academia; Accounting; Address; Affect; American; Animals; Antineoplastic Agents; Apoptosis; Biology; Biomedical Research; Blood; Bone Resorption; Breast; Calcium; Cancer Etiology; Carcinogens; Cause of Death; Cell Line; Cell Surface Receptors; Cell Survival; Cell division; Clinical; Colon Carcinoma; Coma; Data; Dermatology; Development; Discipline; Disease; Disease Resistance; Doctor of Philosophy; Doctor of Veterinary Medicine; EGF gene; Endocrine; Endocrinology; Environment; Epidemic; Epidermal Growth Factor Receptor; Esophagus; Exposure to; Family; Female; Fracture; Funding; Gene Expression; General Population; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Head and neck structure; Health Sciences; Histologic; Hormones; Human; Hypercalcemia; Hypercalcemia of Malignancy; In Vitro; Kidney; Kidney Failure; Laboratories; Life; Ligands; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Messenger RNA; Metastatic Neoplasm to the Bone; Molecular Biology; Molecular Profiling; Molecular Target; Morbidity - disease rate; Mus; National Research Service Awards; Nausea; Occupational Exposure; Ohio; Oligonucleotide Microarrays; Oncogenic; Paraneoplastic Syndromes; Pathway interactions; Patients; Peptides; Phenotype; Plasma; Population Attributable Risks; Postdoctoral Fellow; Principal Investigator; Production; Prostate; Protein Overexpression; Protein Secretion; Protein Tyrosine Kinase; Proteins; Radon; Receptor Activation; Receptor Signaling; Regulation; Relative Risks; Research; Research Personnel; Risk Estimate; Risk-Taking; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Smoking; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Structure of parenchyma of lung; Students; Symptoms; Syndrome; Testing; Time; Translating; Translations; Tyrosine Kinase Inhibitor; Unconscious State; United States; Universities; Woman; Xenograft Model; Xenograft procedure; autocrine; cancer care; cancer cell; cancer epidemiology; career; chemotherapy; clinical application; college; design; in vivo; innovation; keratinocyte; lung Carcinoma; mRNA Expression; mRNA Stability; men; mortality; mouse model; oncology; paracrine; parathyroid hormone-related protein; professor; programs; protein expression; receptor; skills; small molecule; tumor; uncontrolled cell growth

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.

描述（由申请人提供）： 格温多伦·洛奇D.V.M.，医学硕士，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，以支持学术界和生物医学研究的职业生涯。Gwendolen Lorch博士获得了美国兽医皮肤病学院的委员会认证（2001年）。Lorch博士目前是NRSA博士后研究员和博士俄亥俄州州立大学兽医生物科学系的学生。完成博士学位后，Lorch博士将被任命为兽医生物科学系的研究助理教授。她的研究目标是调查表皮生长因子受体（EGFR）激酶信号，导致干扰信号转导和增加甲状旁腺相关蛋白（PTHrP）的表达和恶性肿瘤（HHM）的体液性高钙血症在肺SCC。该项目将具有直接的临床应用，因为鉴定导致PTHrP过表达的失调的致癌蛋白酪氨酸激酶（PTK）将有助于鉴定有效和特异性的PTK抑制剂。 PTHrP最初被认为是导致HHM的因素，并且由所有SCC产生。PTHrP在癌症和正常生物学中具有重要作用，因为除了其作为旁分泌和内分泌激素的功能之外，它还调节细胞分裂、分化和凋亡。Lorch博士研究的重要新数据显示，EGFR信号传导诱导肺SCC中PTHrP表达。待检验的总体假设是EGF配体以自分泌方式与EGFR一起调节肺SCC中PTHrP的表达并诱导HHM的发展。目的1研究EGFR信号通路对人鳞状细胞癌细胞PTHrP基因表达及mRNA稳定性的影响。目的2将评估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，使用异种移植模型和肺SCC细胞系。目的3将通过测量治疗和对照高钙血症小鼠肺SCC模型中表达的基因来鉴定EGFR下游在PTHrP调节和HHM诱导中重要的分子靶点。该项目的大量初步数据已经完成。 兽医生物科学系是六个OSU健康科学学院中成功的学术部门，拥有30名在内分泌学，分子生物学，实验病理生物学，肿瘤学和其他学科的研究人员。托马斯罗索尔的实验室，D.V.M.，博士（申办者）和John Foley博士（共同赞助者）提供一个良好的环境，发展必要的技能，博士Lorch成为一个独立的科学家。 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量存在，并且在许多癌症中具有异常激活，导致细胞的快速不受控制的生长。此外，该提案旨在确定EGFR如何调节肺癌中PTHrP的过度产生并导致危及生命的钙水平升高。我们试图确定特定的细胞信号蛋白，有助于过度PTHrP，这可能是抗癌药物设计的候选目标，并最终限制癌细胞的生存，生长和扩散。研究结果将被转化，以提高全球人类和动物癌症护理的标准。