Measuring and Modulating DNA Damage Surveillance Pathways

测量和调节 DNA 损伤监测途径

基本信息

批准号：
10617737
负责人：
ERIC T. KOOL
金额：
$ 47.84万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617737
关键词：
Address Affect Animal Disease Models Assessment tool Basic Science Biological Biological Assay Biological Models Biological Testing Cancer Etiology Cancer Patient Cell Culture Techniques Cell Line Cell model Cells Cessation of life Chemicals Chemoprevention Clinical Clinical Research Colorectal Cancer Communities Cytosine DNA DNA Damage DNA Repair DNA Repair Enzymes DNA Repair Pathway DNA Sequence Alteration Deamination Development Diagnosis Disease Drug resistance Enzymes Genes Genetic Predisposition to Disease Growth Heart High-Risk Cancer Image Incidence Inflammation Inflammatory Intestines Lead Malignant Neoplasms Measures Molecular Molecular Target Mus Mutagenesis Mutation Neoplasm Metastasis OGG1 gene Outcome Pathway interactions Patients Persons Point Mutation Population Populations at Risk Prevention Prevention strategy Reporter Research Research Personnel Risk Solid Neoplasm Source Specimen Syndrome Testing Tissues Work adverse outcome anticancer research brca gene cancer drug resistance cancer prevention cancer therapy clinically relevant enzyme activity experience high risk innovation malignant breast neoplasm mouse model novel oxidative damage polyposis precision medicine prevent repair enzyme repaired small molecule tool tumor tumorigenesis whole genome

项目摘要

The formation of mutations in cellular DNA lies at the heart of cancer and its treatment. Patients diagnosed with the deadliest solid tumors undergo treatment based on the alterations of DNA sequence in their cancer, and further mutations that occur during treatment cause all-too-common adverse outcomes, including the emergence of drug resistance and metastasis. Of course, these DNA alterations are responsible for the genesis of malignancies in the first place, as accumulated mutations in driver genes lead to uncontrolled growth. Strategies for suppressing mutagenesis can be important for preventing cancer in at-risk populations, and for limiting the emergence of drug resistance and metastasis in existing cancer patients. Here we propose to test a new, molecularly targeted approach to agents that suppress this adverse mutagenesis. Our strategy is based on the most common molecular origins of these cancers: namely, point mutations that arise from specific forms of DNA damage. Our specific aims for the four-year term of the project are to develop new probes to quantify DNA damage in cells and tissues; to identify and develop new small- molecule activators of the repair enzymes that repair the most common sources of mutations; to test whether upregulating DNA repair can suppress the emergence of cancer drug resistance; and to test whether we can lower the incidence of cancer in tumor-prone mice. In progress leading up to this proposal, we have devised several novel and sensitive chemical probes as first-in-class reporters that can measure the cellular activities of multiple DNA repair enzymes. We have employed these probes in clinically relevant studies of cell and tumor specimens, and in investigating connections between inflammation and DNA repair in animal models of disease. In addition, we have used these probes to develop new small-molecule modulators of these pathways, including, excitingly, the only known activators of some of these enzymes. Putting our experience together, we have developed new hypotheses regarding how upregulating the activities of these pathways via small molecules can provide biologically important, and potentially clinically useful, outcomes in cancer. This research is important because it addresses the possibility of preventing common and deadly cancers that remain difficult to treat. In addition, our team will develop molecular tools, including probes, assays, and cell lines, that are likely to be useful to the cancer research community as a whole. Our research plan is innovative in several ways: it will develop and apply new molecular tools for assessing damage and repair pathways; it will lead to the development of the first small-molecule activators of multiple repair enzymes; and it tests new hypotheses regarding how modulating repair activities will be helpful in treatment - and even prevention - of these serious malignancies.

细胞 DNA 突变的形成是癌症及其治疗的核心。确诊患者最致命的实体瘤接受基于癌症 DNA 序列改变的治疗，治疗期间发生的进一步突变会导致非常常见的不良后果，包括耐药性和转移的出现。当然，这些 DNA 改变是造成这种现象的原因。首先是恶性肿瘤的发生，因为驱动基因中累积的突变导致不受控制的生长。抑制突变的策略对于预防高危人群的癌症非常重要，以及限制现有癌症患者耐药性和转移的出现。在这里，我们建议测试一种新的分子靶向方法来抑制这种不利的药物诱变。我们的策略基于这些癌症最常见的分子起源：即，点由特定形式的 DNA 损伤引起的突变。我们该项目四年期限的具体目标将开发新的探针来量化细胞和组织中的 DNA 损伤；识别和开发新的小型修复酶的分子激活剂，可修复最常见的突变源；测试是否上调DNA修复可以抑制癌症耐药性的出现；并测试我们是否可以降低易患肿瘤的小鼠的癌症发病率。在提出该提案的过程中，我们设计了几种新颖且灵敏的化学探针：一流的报告基因，可以测量多种 DNA 修复酶的细胞活性。我们有将这些探针用于细胞和肿瘤样本的临床相关研究，以及调查疾病动物模型中炎症与 DNA 修复之间的联系。此外，我们还使用了这些探针用于开发这些途径的新小分子调节剂，令人兴奋的是，其中包括唯一的其中一些酶的已知激活剂。综合我们的经验，我们开发了新的关于如何通过小分子上调这些途径的活性的假设癌症中具有重要生物学意义且具有潜在临床用途的结果。这项研究很重要，因为它解决了预防常见和致命癌症的可能性仍然难以治疗。此外，我们的团队将开发分子工具，包括探针、分析和细胞系，可能对整个癌症研究界有用。我们的研究计划是在多个方面具有创新性：它将开发和应用新的分子工具来评估损伤和修复途径；它将导致第一个多种修复酶小分子激活剂的开发；和它测试了关于调节修复活动如何有助于治疗的新假设，甚至预防 - 这些严重的恶性肿瘤。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanism-Based Strategy for Optimizing HaloTag Protein Labeling.

基于机制的 HaloTag 蛋白标记优化策略。

DOI：
发表时间：
2022-06-27
期刊：
影响因子：
8
作者：
Marques, Sérgio M;Slanska, Michaela;Chmelova, Klaudia;Chaloupkova, Radka;Marek, Martin;Clark, Spencer;Damborsky, Jiri;Kool, Eric T;Bednar, David;Prokop, Zbynek
通讯作者：
Prokop, Zbynek

Luminescent Carbon Dot Mimics Assembled on DNA.

DNA 上组装的发光碳点模拟物。