Elucidating the Molecular Mechanism of TRIP13-mediated Radiation Resistance in Oral Squamous Cell Carcinoma

阐明 TRIP13 介导的口腔鳞状细胞癌放射抗性的分子机制

基本信息

批准号：
10649402
负责人：
Marsha-Kay Norissa Deanna Hutchinson
金额：
$ 5.35万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649402
关键词：
ATP phosphohydrolase ATPase Domain Address Antibodies Attenuated Binding Biological Cell Line Cell Survival Cetuximab Complex DNA DNA Damage DNA-dependent protein kinase Data Disease Double Strand Break Repair Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exposure to FDA approved Failure Genetic Engineering Goals Human Cell Line Hydrolysis Immunohistochemistry Impairment In Vitro Incidence Investigation Knowledge Laboratories Malignant Epithelial Cell Malignant Neoplasms Mediating Modality Molecular Mus Mutation Nonhomologous DNA End Joining Oncogenic Pathway interactions Patient-Focused Outcomes Patients Peptides Phosphorylation Pilot Projects Proteins RIPK1 gene Radiation Radiation Induced DNA Damage Radiation Tolerance Radiation induced double strand break Radiation therapy Radiation-Sensitizing Agents Recurrence Recurrent tumor Role Site Survival Rate Testing Thyroid Hormone Receptor Western Blotting Work advanced disease aggressive therapy cytotoxic genetically modified cells improved in vivo insight irradiation mouth squamous cell carcinoma neoplastic cell novel novel strategies overexpression patient prognosis predictive marker radiation resistance radiation response radioresistant repaired tumor

ATP phosphohydrolase ATPase Domain Address Antibodies Attenuated Binding Biological Cell Line Cell Survival Cetuximab Complex DNA DNA Damage DNA-dependent protein kinase Data Disease Double Strand Break Repair Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exposure to FDA approved Failure Genetic Engineering Goals Human Cell Line Hydrolysis Immunohistochemistry Impairment In Vitro Incidence Investigation Knowledge Laboratories Malignant Epithelial Cell Malignant Neoplasms Mediating Modality Molecular Mus Mutation Nonhomologous DNA End Joining Oncogenic Pathway interactions Patient-Focused Outcomes Patients Peptides Phosphorylation Pilot Projects Proteins RIPK1 gene Radiation Radiation Induced DNA Damage Radiation Tolerance Radiation induced double strand break Radiation therapy Radiation-Sensitizing Agents Recurrence Recurrent tumor Role Site Survival Rate Testing Thyroid Hormone Receptor Western Blotting Work advanced disease aggressive therapy cytotoxic genetically modified cells improved in vivo insight irradiation mouth squamous cell carcinoma neoplastic cell novel novel strategies overexpression patient prognosis predictive marker radiation resistance radiation response radioresistant repaired tumor

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项目摘要

Oral squamous cell carcinoma (OSCC) is a common and aggressive cancer. In recent years, despite significant effort to understand the pathobiology of the disease, there has been only marginal improvement in patient prognosis. Radiation is one of the chief treatment modalities for OSCC, but radiation resistance has led to a high incidence of locoregional failure and tumor recurrence. Radiation is incredibly cytotoxic and has the potential to completely annihilate tumors via induction of lethal double strand breaks (DSBs) in DNA. To adequately exploit the benefits of radiation and improve patient outcomes, a thorough understanding of the molecular mechanisms of radiation resistance is essential. Non-homologous end joining (NHEJ) is the main repair pathway for radiation- induced DSBs. The high incidence of locoregional failure and tumor recurrence after radiation is likely a reflection of efficient repair. Therefore, a keen understanding of how NHEJ occurs is vital to developing novel strategies to increase radiation sensitivity. Our laboratory identified thyroid hormone receptor interacting protein 13 (TRIP13) as an oncogenic ATPase that promotes NHEJ and radiation resistance in OSCC. The goal of this study is to delineate the molecular mechanism of TRIP13-mediated NHEJ that enhances radiation resistance. Pilot data show that phosphorylation of TRIP13 is essential for radioresistance. Moreover, loss of the ATPase activity of TRIP13 sensitizes OSCC to radiation; ATPases are frequently involved in assembly of biological complexes. Therefore, the central hypothesis of the proposed study is that phosphorylation-induced ATPase activity of TRIP13 is necessary for DNA-PK complex formation in NHEJ, thereby promoting radiation resistance in OSCC. To test this hypothesis, we propose the following specific aims: 1) to explore the extent to which phosphorylation of TRIP13 promotes NHEJ via induction of its ATPase activity; 2) to investigate the extent to which the ATPase activity of TRIP13 promotes radiation resistance and 3) to validate pTRIP13 as a predictive marker of radiation resistance. To address these aims, we will engineer genetically modified cell lines to dissect the mechanism of radiation resistance in vitro and in in vivo. These aims will elucidate the molecular mechanism behind TRIP13- mediated radiation resistance and will investigate phospho-TRIP13 as a novel predictive marker of radiation resistance.

口服鳞状细胞癌（OSCC）是一种常见和侵略性癌症。近年来，尽管很重要努力了解该疾病的病理学，患者只有微不足道的改善预后。辐射是OSCC的主要治疗方式之一，但耐药性导致了高度局部衰竭和肿瘤复发的发生率。辐射具有令人难以置信的细胞毒性，并且有可能通过在DNA中诱导致命的双链断裂（DSB），完全消灭了肿瘤。充分利用辐射的好处并改善患者的结果，对分子机制有透彻的了解辐射阻力是必不可少的。非同源末端连接（NHEJ）是辐射的主要修复途径 - 诱导的DSB。辐射后局部衰竭和肿瘤复发的高发生率可能是反射有效维修。因此，对NHEJ的发生的敏锐理解对于制定新型策略至关重要提高辐射灵敏度。我们的实验室确定甲状腺激素受体相互作用蛋白13（Trip13）作为促进OSCC中NHEJ和辐射抗性的致癌ATPase。这项研究的目的是描述Trip13介导的NHEJ的分子机制，从而增强了辐射抗性。试点数据表明Trip13的磷酸化对于放射线至关重要。此外，丧失ATPase活性 Trip13将OSCC敏感到辐射； ATPases经常参与生物复合物的组装。因此，拟议研究的中心假设是磷酸化诱导的ATPase活性 TRIP13对于NHEJ中的DNA-PK复合物形成是必需的，从而促进OSCC中的辐射抗性。为了检验这一假设，我们提出了以下特定目的：1）探索磷酸化的程度 Trip13的of通过诱导其ATPase活性来促进NHEJ； 2）研究ATPase的程度 TRIP13的活性促进辐射电阻，3）验证PTRIP13作为辐射的预测标记反抗。为了解决这些目的，我们将设计基因修饰的细胞系以剖析体外和体内耐药性。这些目标将阐明Trip13-背后的分子机制介导的辐射抗性，并将研究磷酸-TRIP13作为辐射的新预测标记反抗。