Targeting Cancer with Telomerase Interference

通过端粒酶干扰靶向癌症

基本信息

批准号：
7682952
负责人：
Amir Goldkorn
金额：
$ 13.08万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682952
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.

项目概要：我的目标是成为一名独立的医师科学家，从事基础研究和临床研究关联。迄今为止，我在肿瘤医学和癌症研究方面的培训已经奠定了坚实的基础为了学术生涯。这项拨款提案将使我能够过渡到独立通过以实验室研究为重点并辅以研讨会和科学的综合计划讨论论坛。所有活动都将在我的赞助商伊丽莎白的指导下进行布莱克本，并得到了由我所在领域的高级教师专家组成的咨询委员会的指导。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，因为，相对于与正常细胞相比，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端粒酶靶向基因结构，可抑制癌细胞增殖具体而有效。该构建体采用双管齐下的方法：它使用 siRNA 来敲入下调内源性 hTer，并在其位置编码突变的端粒酶 RNA 亚基 (MT-hTer)。当在癌细胞系中表达时，MT-hTer 与 hTERT 整合并形成异常的端粒酶可诱导快速 DMA 损伤、细胞凋亡和细胞周期停滞。在这个提案中，我们假设 MT-hTer 引发的快速而强烈的细胞凋亡反应可以有效抑制肿瘤生长。该假设将通过机制和转化研究进行检验。具体来说我们将： 1. 鉴定 MT-hTer 诱导的细胞凋亡级联的蛋白质成分； 2. 使用肿瘤- 衍生的原代细胞培养模型来评估 MT-hTer 单独和在与既定疗法相结合； 3. 使用小鼠模型测试 MT- 的肿瘤抑制作用 hTer 通过癌症靶向免疫脂质体进行全身递送。关联：拟议的项目将描述一种能够杀死多种端粒酶的新型端粒酶靶向剂。癌细胞类型。将探讨其作用机制及其抑制转移性癌症的能力将对小鼠进行测试，从而开发出一种有前途的新治疗策略。