Targeting Cancer with Telomerase Interference

通过端粒酶干扰靶向癌症

基本信息

批准号：
7921784
负责人：
Amir Goldkorn
金额：
$ 10.8万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7921784
关键词：
Address Adopted Advisory Committees Antineoplastic Agents Apoptosis Apoptotic Applications Grants Automobile Driving Basic Science Biophotonics Cancer cell line Carcinoma Catalytic Domain Cell Cycle Arrest Cell Line Cell Proliferation Cells Chromosomes Complex DNA DNA Damage DNA Sequence Data Development Disease Disseminated Malignant Neoplasm Eating Enzymes Faculty Foundations Gene Targeting Goals Human Image Immunoliposome Laboratories Liposomes Malignant Neoplasms Measures Mediating Medical Oncology Mentorship Mitochondria Modeling Morbidity - disease rate Mus Mutate Neoplasm Metastasis Normal Cell Pathway interactions Pharmaceutical Preparations Physicians Play Pre-Clinical Model Primary Cell Cultures Primary Neoplasm Principal Investigator Proteins RNA RNA-Directed DNA Polymerase Relative (related person)Research Research Personnel Ribonucleoproteins Role Scheme Scientist Signal Transduction Stem cells TERF1 gene Telomerase Telomerase RNA Component Telomerase inhibition Testing Therapeutic Tissues Training Tumor-Derived Work Xenograft Model anticancer research bak protein base cancer cell cancer stem cell cancer therapy career cell type chemotherapy clinically relevant efficacy testing in vivo insight interest killings knock-down mortality mouse model mutant novel novel strategies oncology pre-clinical programs research study response telomerase reverse transcriptase telomere therapeutic target tissue culture translational study treatment strategy tumor tumor growth

项目摘要

Project Summary: My goal is to become an independent physician-scientist engaged in basic research with clinical relevance. My training thus far in medical oncology and cancer research has laid a strong foundation for an academic career. This grant proposal will enable me to make the transition to independence through an integrated program focused on lab research and supplemented by seminars and scientific discussion forums. All activities will be conducted under the mentorship of my sponsor, Elizabeth Blackburn, and with the guidance of an Advisory Committee of senior faculty experts in my field. My research interests are in the field of telomerase and cancer. Telomerase enzyme lengthens and protects the telomeres at the ends of chromosomes through the combined action of its catalytic subunit (hTERT) and its RNA subunit (hTer). Telomerase is an attractive therapeutic target because, relative to normal cells, telomerase is highly activated in cancer cells and critical to cancer cell proliferation. Our lab has developed a novel telomerase-targeting gene construct that inhibits cancer cell proliferation specifically and effectively. The construct takes a two-pronged approach: It employs siRNA to knock down endogenous hTer, and it encodes a mutated telomerase RNA subunit (MT-hTer) in its place. When expressed in cancer cell lines, MT-hTer integrates with hTERT and forms an aberrant telomerase enzyme that induces rapid DMAdamage, apoptosis, and cell cycle arrest. In this proposal, we hypothesize that the rapid and robust apoptotic response elicited by MT-hTer can effectively inhibit tumor growth. This hypothesis will be tested using mechanistic and translational studies. Specifically we will: 1. Identify the protein components of the MT-hTer-induced apoptotic cascade; 2. Use tumor- derived primary cell culture models to assess the pro-apoptotic effects of MT-hTer alone and in combination with established therapies; and 3. Use mouse models to test for tumor-inhibition by MT- hTer delivered systemically with cancer-targeting immunoliposomes. Relevance: The proposed project will characterize a novel telomerase-targeting agent capable of killing a variety of cancer cell types. Its mechanism of action will be explored, and its ability to inhibit metastatic cancers in mice will be tested, thus developing a promising new treatment strategy.

项目摘要：我的目标是成为一名独立的医师科学家，从事临床研究的基础研究关联。迄今为止，我在医学肿瘤学和癌症研究方面的培训为我奠定了坚实的基础在学术生涯中。该赠款提案将使我能够过渡到独立性通过专注于实验室研究的综合计划，并补充了研讨会和科学讨论论坛。所有活动将在我的赞助商伊丽莎白的指导下进行布莱克本（Blackburn），并在我领域高级教师专家的咨询委员会的指导下。我的研究兴趣是端粒酶和癌症领域。端粒酶延长，并通过其催化亚基的联合作用保护染色体末端的端粒（HTERT）及其RNA亚基（HTER）。端粒酶是一个有吸引力的治疗靶点正常细胞，端粒酶在癌细胞中高度激活，对癌细胞增殖至关重要。我们的实验室开发了一种新型的端粒酶靶向基因构建体，该构建体抑制癌细胞增殖具体有效。该构造采用了两管齐的方法：它采用sirna敲门向下内源性hter，并在其位置编码突变的端粒酶RNA亚基（MT-HET）。当在癌细胞系中表达时，mt-thter与HTERT整合并形成异常端粒酶诱导快速的DMADAMAGE，凋亡和细胞周期停滞。在此提案中，我们假设Mt-Hter引起的快速，稳健的凋亡反应可以有效抑制肿瘤生长。该假设将使用机械和翻译研究进行检验。特别是我们意志：1。识别MT刺激诱导的凋亡级联反应的蛋白质成分； 2。使用肿瘤 - 衍生的原发性细胞培养模型，以评估单独MT和IN的促凋亡作用结合既定疗法； 3。使用小鼠模型测试MT-的肿瘤抑制作用 hter通过靶向癌症的免疫脂质体系统地交付。关联：拟议的项目将表征一种新颖的端粒酶靶向剂，能够杀死各种癌细胞类型。将探索其作用机理，并抑制转移性癌症的能力将测试小鼠，从而制定有希望的新治疗策略。