Radiation-induced molecular targets

辐射诱导的分子靶标

• 批准号: 9779681
• 负责人: Norman Coleman
• 金额: $ 125.4万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9779681
• 关键词: Abscopal effect; Biological Markers; CCR; Cardiovascular system; Categories; Cells; Clinic; Collaborations; Combined Modality Therapy; Complex; Cyclooxygenase Inhibitors; Data; Development; Diagnosis; Disasters; Dose; Dose Fractionation; Dose-Limiting; Drug toxicity; Drug-sensitive; Endothelial Cells; Epigenetic Process; Event; Extramural Activities; Fingerprint; Gene Chips; Gene Expression; Genes; Genetic Transcription; Health; Hour; Human; Immune; Immune Response Genes; Immune response; Immunotherapy; Injury; Intensity-Modulated Radiotherapy; Kidney; Laboratories; Lead; Legal patent; Magnetic Resonance Imaging; Malignant Neoplasms; Manuscripts; Medical; Medical center; Messenger RNA; MicroRNAs; Modality; Molecular; Molecular Target; Names; National Institute of Allergy and Infectious Disease; Non-Steroidal Anti-Inflammatory Agents; Normal tissue morphology; Nuclear; Nuclear Radiology; Ontology; PC3 cell line; PTGS2 gene; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Policies; Preclinical Drug Evaluation; Process; Proteins; Proteomics; Publishing; Radiation; Radiation Injuries; Radiation Oncology; Radiation therapy; Radiology Specialty; Radiosurgery; Readiness; Regimen; Resources; Science; Services; Small Interfering RNA; Systems Analysis; Techniques; Technology; Terrorism; Testing; Thinking; Time; Toxic effect; Triage; United States National Institutes of Health; Work; anti-cancer; base; biodosimetry; biological adaptation to stress; cancer care; cancer cell; cell killing; citrin; clinically relevant; gastrointestinal; image guided radiation therapy; immunoregulation; in vitro testing; in vivo; inhibitor/antagonist; interest; mass casualty; metabolic abnormality assessment; metabolomics; molecular drug target; molecular targeted therapies; mouse model; novel; point-of-care diagnostics; pre-clinical; programs; protein expression; response; targeted treatment; tumor

The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on "radiation inducible molecular targets" that is, exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy. In essence, radiation would set up the tumor for enhanced drug killing. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1, 2 Gy x5, 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated and published that the cells post-radiation are more drug sensitive for at least 1 drug in the short term and 1 drug 60 days later, indicating cellular adaptation. This is now published. The novel observation of an inducible target has broad implications for cancer adaptation to treatment for both molecular-targeted therapy and immunotherapy. We are now studying combination therapy of targets and "synthetic lethality" We have made significant progress in studying the inducible mRNA, miRNA, proteins and metabolomics changes. Projects now in progress include studying metabolomic changes, in vivo SD and MF for PC3 cells, and epigenetic changes. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation, our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control, including direct and abscopal effects. With a recently successful laboratory review we are expanding collaborations by which we can possibly detect the adaptive changes working with Jim Mitchell of RBB and Deb Citrin or ROB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation Closely related to this work are efforts being done on identifying biomarkers of radiation injury. This relates to cancer and also to work I do in the Office of the Assistant Secretary for Preparedness and Response in Health and Human Services (HHS). I am heading a group developing civilian medical response planning for radiological and nuclear terrorism and other events. This involves planning, policy, and normal tissue injury-related science. Medical countermeasures are being developed through NIAID support in the Centers for Medical Countermeasures Against Radiation (CMCR). This overall program has major impact to U.S. preparedness and also has a spin-off for normal tissue injury from radiation and the potential for post-exposure mitigators and treatments. We are working with other agencies (NIAID and Dept of Defense) on the potential of bringing these mitigators into cancer care. The critical importance of the NCI- HHS linkage is bringing up-to-date scientfic thinking to medical countermeasure development and diagnosis - A more direct linkage between the NIH and DHHS programs is our work on biomarkers for biodosimetry supported by NIAID. This is looking at RNA expression at various times after a range of whole body doses, currently using a mouse model. The importance of having an accurate point-of-care diagnostic with which to triage potential radiation casualties cannot be over estimated given the potential size of a nuclear/radiological disaster. The biomarker work is supported by NIAID and BARDA (of ASPR).

我们实验室计划的长期重点是辐射和微环境应激反应。我们现在专注于“辐射诱导的分子靶点”，即探索使用多分割(MF)辐射以及更高的单次剂量(SD)来诱导使细胞对分子靶向治疗敏感的细胞表型。从本质上讲，辐射会使肿瘤增强药物杀伤力。该项目现在已经证明，不同剂量的辐射-MF和SD-(10Gyx1、2GyX5、1Gyx10和低至0.5Gyx10)产生不同的表型。我们已经证明并发表了辐射后的细胞对至少一种药物在短期内和60天后对一种药物的敏感性更高，这表明细胞适应。这本书现已出版。对可诱导靶点的新观察对分子靶向治疗和免疫治疗的癌症适应具有广泛的意义。我们正在研究靶点和“合成杀伤力”的联合治疗。我们在研究诱导型mRNA、miRNA、蛋白质和代谢组学变化方面取得了重大进展。目前正在进行的项目包括研究代谢变化，体内PC3细胞的SD和MF，以及表观遗传学变化。我们现在正在与复杂系统分析专家合作，以确定靶向的路径，并研究辐射和药物的时机(S)。随着对免疫调节的主要兴趣，我们的工作对可用于肿瘤控制的免疫增强的辐射剂量和分割有重大影响，包括直接和非局部影响。随着最近一项成功的实验室审查，我们正在扩大合作，通过这些合作，我们可能会检测到适应性变化，与RBB的Jim Mitchell和Deb Citrin或RBB的Rob和Murali Cherukuri合作，他们已经使用超极化MRI技术来研究与这项工作密切相关的代谢适应，正在努力识别辐射损伤的生物标记物。这与癌症有关，也与我在卫生与公共服务部门负责准备和反应的助理秘书办公室(HHS)所做的工作有关。我正在领导一个小组，制定针对放射性和核恐怖主义以及其他事件的民用医疗反应计划。这涉及规划、政策和与正常组织损伤相关的科学。通过辐射医学对策中心(CMCR)的NIAID支持，正在制定医学对策。这一整体计划对美国的准备工作有重大影响，还包括辐射造成的正常组织损伤的副产品，以及辐射后缓解和治疗的可能性。我们正在与其他机构(NIAID和国防部)合作，研究将这些缓释剂引入癌症护理的可能性。NCI-HHS联系的关键是为医学对策的制定和诊断带来最新的科学思维--NIH和DHHS项目之间更直接的联系是我们在NIAID支持的生物剂量学生物标志物方面的工作。这是在一系列全身剂量后的不同时间观察RNA的表达，目前使用的是小鼠模型。鉴于核/辐射灾难的潜在规模，对潜在的辐射伤亡进行分类的准确的护理点诊断的重要性怎么估计都不为过。生物标记物工作得到NIAID和BARDA(ASPR)的支持。