Measuring and Modulating Oxidative DNA Damage Surveillance Pathways

测量和调节氧化 DNA 损伤监测途径

• 批准号: 9924487
• 负责人: ERIC T. KOOL
• 金额: $ 49.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924487
• 关键词: 8-hydroxyguanosine; Address; Affect; Basic Science; Biological; Biological Assay; Cell Line; Cells; Cessation of life; Chemicals; Clinical; Colorectal Cancer; Communities; DNA; Development; Disease; Down-Regulation; Drug Industry; Enzyme Activators; Enzymes; Fluorescence; Growth and Development function; Guanine; Health; Human; Immunotherapy; Individual; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Methods; Modeling; Molecular; Molecular Probes; Mutagenesis; Nucleotides; OGG1 gene; Outcome; Pathway interactions; Patients; Prevention; Reactive Oxygen Species; Reporter; Research; Research Personnel; Role; Specimen; System; Testing; Tissues; Toxic effect; Tumor Cell Line; Tumor Tissue; Up-Regulation; Work; anticancer research; cancer therapy; combat; design; enzyme activity; inhibitor/antagonist; innovation; neoplastic cell; novel; oxidation; oxidative DNA damage; oxidative damage; precision medicine; prevent; rapid growth; repaired; scaffold; screening; small molecule; small molecule inhibitor; tool; tumor; tumor growth; tumorigenesis

Project Summary Despite exciting progress made recently in precision medicine, several common cancers remain difficult to treat, including lung, colorectal, and pancreatic cancer, which together account for over 200,000 deaths annually. One common molecular factor in these tumors is high levels of reactive oxygen species, which lead to oxidative damage in DNA – most notably, 8-oxoguanine (8-OG), which is both toxic and mutagenic. As a result, tumor cells evolve strategies to support rapid growth, and thus often misregulate the enzymes that combat this damage: namely MTH1 and OGG1, which remove 8-OG from the nucleotide pool and from DNA itself. We hypothesize that developing approaches to control the activities of these enzymes will provide new and promising strategies for controlling tumor growth. However, until very recently no one has been able to measure or modulate these enzymes' activities. In preliminary work leading up to this proposal, novel and sensitive chemical probes have been devised that are the only existing reporters that can measure the cellular activities of MTH1 and OGG1. In addition, these probes have been used to identify new small-molecule modulators of these pathways, including, excitingly, the only known activators of the two enzymes. Third, new hypotheses have been developed regarding how modulating the activities of these pathways via small molecules, singly or in combination, can provide biologically important, and potentially clinically useful, outcomes in cancer. The Kool/Ford collaborative team will develop and employ these molecular tools to investigate the promise of modulating these important repair pathways. The specific aims for the four-year term of the project are to develop new probes to quantify repair activities in tumor cells and tissues; to identify and develop new small-molecule inhibitors and activators of the enzymes; to test novel biological hypotheses regarding how targeted up- or down-regulation may suppress tumor growth; and to test a new hypothesis for preventing tumorigenesis in individuals who are genetically susceptible to developing cancer. This research is important because it addresses multiple common and deadly cancers that remain difficult to treat. In addition, the collaborative team will develop several molecular tools that are likely to be useful to the cancer research community as a whole. Moreover, if successful, this work may lead to new targeted strategies for cancer treatment, and practical methods for evaluating patients for these therapies. This research plan is innovative in several ways: it will develop and apply novel molecular tools for assessing damage repair pathways; it will lead to the development of the only known small-molecule activators of damage repair, and it presents new hypotheses regarding how modulating repair activities will be helpful in treatment - and even prevention - of these serious malignancies.

项目摘要 尽管最近在Precision医学中取得了令人兴奋的进步，但几种常见的癌症仍然困难 治疗，包括肺，结直肠癌和胰腺癌，共同占了200,000多个 每年死亡。这些肿瘤中的一个常见分子因子是高水平的活性氧， 导致DNA氧化损伤 - 最值得注意的是8-氧气（8-OG），这既有毒又是 诱变。结果，肿瘤细胞发展了支持快速生长的策略，因此常常不正常 对抗这种损害的酶：MTH1和OGG1，从 核苷酸池和DNA本身。我们假设开发控制活动的方法 这些酶将为控制肿瘤生长提供新的和有希望的策略。但是，直到 最近，没有人能够测量或调节这些酶的活性。 在此提案的初步工作中，新颖和敏感的化学问题已经存在 设计的是唯一可以测量MTH1和OGG1细胞活动的记者。 此外，这些问题已用于确定这些途径的新小分子调节剂， 令人兴奋的是，这是两种酶的唯一已知的激活剂。第三，新假设是 开发了有关如何通过小分子或单独或IN调节这些途径的活动的开发 组合可以在癌症中提供生物学上重要且可能在临床上有用的结果。 库尔/福特协作团队将开发并使用这些分子工具来调查 有望调节这些重要的维修途径。四年期的具体目标 项目将开发新的问题来量化肿瘤细胞和组织中的修复活动；识别和 开发新的小分子抑制剂和酶的活化剂；测试新的生物学假设 关于靶向上调或下调如何抑制肿瘤的生长；并检验一个新的假设 用于预防遗传上易感癌症的个体的肿瘤发生。 这项研究很重要，因为它解决了仍然存在的多种常见和致命的癌症 很难治疗。此外，协作团队将开发几种可能会有可能的分子工具 对整个癌症研究界有用。而且，如果成功的话，这项工作可能会导致 癌症治疗的新目标策略和评估患者的实用方法 疗法。该研究计划在几种方面具有创新性：它将开发和应用新颖的分子工具 用于评估损害修复途径；它将导致唯一已知的小分子的发展 损害维修的激活因子，并提出了有关调节活动如何调节活动的新假设 这些严重的恶性肿瘤将有助于治疗甚至预防。