Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets

作为癌基因和治疗靶点的蛋白水解受体

基本信息

批准号：
8791266
负责人：
Tanya I Stoyanova
金额：
$ 13.89万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791266
关键词：
Accounting Adenocarcinoma Cell Antibodies Area Automobile Driving Award Benign Biochemical Biochemistry Bioinformatics Biological Assay Biometry Blocking Antibodies Calculi California Cancer Biology Cause of Death Cell Nucleus Cell Proliferation Cell surface Cells Cellular biology ChIP-seq Cleaved cell Clinical Pathology Colorectal Cancer Combined Modality Therapy DNA-Protein Interaction Data Analyses Development Down-Regulation ERBB2 gene Epithelial Epithelium Exhibits Extracellular Domain Faculty Gene Expression Profile Gene Targeting Goals Growth Head Health High-Throughput Nucleotide Sequencing Human Human Genetics Integral Membrane Protein Laboratories Los Angeles MS4A1 gene Malignant Neoplasms Malignant neoplasm of prostate Medicine Membrane Mentors Methods Modeling Molecular Non-Hodgkin&apos s Lymphoma Nuclear Oncogenes Oncogenic Pathogenesis Pathologist Pathology Pathway interactions Pharmacology Phase Positioning Attribute Prostate Prostatic Neoplasms Proteolysis Proto-Oncogene Proteins c-akt Public Health RNA Sequence Analysis Receptor Protein-Tyrosine Kinases Research Research Personnel Role Sampling Science Scientist Signal Transduction Site Surface Testing Therapeutic Tissue Recombination Tissues Training Transcriptional Regulation Translating Trastuzumab United States Universities Vascular Endothelial Growth Factors anticancer research beta catenin bevacizumab cancer genomics cancer initiation cancer therapy cancer type career castration resistant prostate cancer chromatin immunoprecipitation cohort functional genomics gamma secretase genome wide association study genome-wide human tissue improved in vivo inhibitor/antagonist insight malignant breast neoplasm medical schools metaplastic cell transformation mortality new therapeutic target novel therapeutics oncology professor programs prostate carcinogenesis receptor research study rituximab small molecule success therapeutic target tumor initiation tumor progression tumorigenesis urologic

项目摘要

DESCRIPTION (provided by applicant): My long term career objective is to be an independent investigator in an academic setting studying molecular signaling involved in epithelial tumorigenesis and their potential to be targeted for cancer therapy. The K99/R00 Pathway to Independence Award and the research proposed in this application will be instrumental in my professional development as a scientist and in transitioning to a Faculty Position. ENVIRONMENT. During the mentored K99 phase of the award I will perform the proposed research under the direct guidance of Dr. Witte at the University of California at Los Angeles (UCLA). Dr. Witte is a world- renowned leader in the field of cancer research. Dr. Witte will further my training in cancer biology since his laboratory has developed a unique set of approaches to study prostate cell biology and cancer pathogenesis. I have also assembled an advisory board with a co-mentor and several consultants/collaborators including: Dr. Kurdistani, Professor in the Department of Biological Chemistry at UCLA, is an expert in functional genomics; Dr. Huang, Professor of Pathology and Laboratory Medicine and Director of Urologic Pathology at UCLA, is an expert in prostate clinical-pathology; Dr. Pienta, Professor of Oncology and Pharmacology and Molecular Sciences at Johns Hopkins University, is a leader in the developing of new therapeutic programs for prostate cancer; Dr. Rubin, Professor of Pathology and Laboratory Medicine and Oncology at Weill Cornell Medical College, is an internationally recognized pathologist and a leader in prostate cancer genomics. Dr. Horvath, Professor of Biostatistics and Human Genetics and Head of the Array Data Analysis Group at UCLA, is a leader in developing bioinformatics methods. During the K99 phase of the Award, I will gain training in the areas of functional genomics, and strategies to translate molecular signaling into therapeutics. This training will be a stepping stone for my independent career as a cancer biologist. RESEARCH. I have previously characterized the oncogenic role of the type I transmembrane protein Trop2 in prostate tumorigenesis. My previous studies demonstrated that Trop2 is activated through regulated intramembrane proteolysis resulting in cleavage of Trop2 at two distinct sites. Upon cleavage, the intracellular domain of Trop2 translocates into the nucleus and initiates a downstream signaling cascade driving cellular proliferation and tumor initiation. My recent studies identified Notch1, another type I transmembrane protein regulated through proteolytic cleavages, as a key player in prostate tumorigenesis. My preliminary results point to an existing cross-talk between Trop2 and Notch1 receptors. In Aim 1, I will investigate the functional cooperation between Trop2 and Notch1 receptors in prostate tumor initiation and progression in vivo utilizing the recently established primary human tissue recombination assay. In Aim 2, I will define new downstream targets of Trop2 and identify the biochemical relationship between Trop2 and Notch1 signaling. In Aim 3, I will test combined inhibition of Trop2 and Notch1 signaling as a new therapeutic strategy in cancer.

描述（由申请人提供）：我的长期职业目标是在研究上上皮肿瘤发生涉及的分子信号的学术环境中成为独立研究者，及其针对癌症治疗的潜力。 K99/R00独立奖和本申请中提出的研究将有助于我作为科学家的专业发展以及过渡到教师职位。环境。在奖项的K99阶段，我将在加利福尼亚大学洛杉矶分校（UCLA）的Witte博士的直接指导下进行拟议的研究。 Witte博士是癌症研究领域的世界知名领导者。 Witte博士将进一步进一步接受癌症生物学的培训，因为他的实验室已经开发了一种独特的研究前列腺细胞生物学和癌症发病机理的方法。我还与一个顾问和几位顾问/合作者组建了一个顾问委员会，包括：加州大学洛杉矶分校生物化学系教授库德斯坦尼博士是功能基因组学专家； Huang博士，病理学和实验室医学教授兼加州大学洛杉矶分校的泌尿科病理学主任，是前列腺临床病理学专家；约翰霍普金斯大学肿瘤学和药理学与分子科学教授Pienta博士是开发前列腺癌新治疗计划的领导者； Weill Cornell医学院的病理学和实验室医学和肿瘤学教授Rubin博士是国际认可的病理学家，也是前列腺癌基因组学的领导者。 Horvath博士是UCLA生物统计学和人类遗传学教授，阵列数据分析小组的负责人，是开发生物信息学方法的领导者。在奖项的K99阶段，我将在功能基因组学领域进行培训，以及将分子信号传导转化为治疗剂的策略。这项培训将是我作为癌症生物学家独立职业的垫脚石。研究。我先前曾表征I型跨膜蛋白trop2在前列腺肿瘤发生中的致癌作用。我以前的研究表明，Trop2通过膜内蛋白水解而激活，导致在两个不同位点上的Trop2裂解。裂解后，trop2的细胞内结构域易位到核中，并启动下游信号传导级联驱动细胞增殖和肿瘤起始。我最近的研究确定了Notch1，这是通过蛋白水解裂解调节的另一种I型跨膜蛋白，是前列腺肿瘤发生的关键参与者。我的初步结果表明Trop2和Notch1受体之间的现有串扰。在AIM 1中，我将利用最近建立的原发性人体组织重组测定法研究了前列腺肿瘤起始和体内进展中Trop2和Notch1受体之间的功能合作。在AIM 2中，我将定义Trop2的新下游目标，并确定Trop2和Notch1信号传导之间的生化关系。在AIM 3中，我将测试对Trop2和Notch1信号传导的联合抑制作用，作为癌症的新治疗策略。