Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets

描述（由申请人提供）：我的长期职业目标是成为一名独立的研究者，在学术环境中研究上皮肿瘤发生中涉及的分子信号及其成为癌症治疗靶点的潜力。K99/R00独立之路奖和本申请中提出的研究将有助于我作为一名科学家的专业发展和过渡到教师职位。环境在该奖项的指导K99阶段，我将在加州大学洛杉矶分校（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博士将进一步加强我在癌症生物学方面的培训，因为他的实验室已经开发出一套独特的方法来研究前列腺细胞生物学和癌症发病机制。我还组建了一个顾问委员会，由一位共同导师和几位顾问/合作者组成，包括：UCLA生物化学系教授Kurdistani博士，是功能基因组学专家; UCLA病理学和实验室医学教授兼泌尿病理学主任Huang博士，是前列腺临床病理学专家; Pienta博士是约翰霍普金斯大学肿瘤学、药理学和分子科学教授，是前列腺癌新治疗方案开发的领导者;鲁宾博士是威尔康奈尔医学院病理学和实验室医学及肿瘤学教授，是国际公认的病理学家和前列腺癌基因组学的领导者。Horvath博士，生物统计学和人类遗传学教授，加州大学洛杉矶分校阵列数据分析小组负责人，是开发生物信息学方法的领导者。在该奖项的K99阶段，我将获得功能基因组学领域的培训，以及将分子信号转化为治疗方法的策略。这次培训将是我作为一名癌症生物学家独立职业生涯的垫脚石。research.我以前的特点是致癌作用的I型跨膜蛋白Trop2在前列腺肿瘤发生。我以前的研究表明，Trop2通过调节膜内蛋白水解激活，导致Trop2在两个不同位点裂解。切割后，Trop2的细胞内结构域易位到细胞核中并启动下游信号级联，驱动细胞增殖和肿瘤起始。我最近的研究确定Notch1，另一种I型跨膜蛋白，通过蛋白水解裂解调节，作为前列腺肿瘤发生的关键球员。我的初步结果表明，Trop2和Notch1受体之间存在串扰。在目的1中，我将研究Trop2和Notch1受体之间的功能合作，前列腺肿瘤的启动和发展，在体内利用最近建立的主要人体组织重组试验。在目标2中，我将定义Trop2的新下游靶点，并确定Trop2和Notch1信号传导之间的生化关系。在目标3中，我将测试Trop2和Notch1信号传导的联合抑制作为癌症的新治疗策略。

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.