Radiation-induced molecular targets

辐射诱导的分子靶标

• 批准号: 10262128
• 负责人: Norman Coleman
• 金额: $ 141.66万
• 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/10262128
• 关键词: Abscopal effect; Advisory Committees; Biological; Biological Markers; COVID-19 pandemic; Caring; Cells; Clinical; Collaborations; Combined Modality Therapy; Complex; DU145; Data; Development; Diagnosis; Disaster Planning; Dose; Dose Fractionation; Drug Design; Drug usage; Endothelial Cells; Epigenetic Process; Event; Genes; Genetic Transcription; Health; Healthcare; Human; Immune; Immune response; Immunotherapy; Intensity-Modulated Radiotherapy; LNCaP; Laboratories; Magnetic Resonance Imaging; Malignant Neoplasms; Medical; Medical center; Messenger RNA; MicroRNAs; Miniature Swine; Molecular; Molecular Target; National Institute of Allergy and Infectious Disease; Normal tissue morphology; Nuclear; Nuclear Radiology; Ontology; PC3 cell line; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Policies; Proteins; Proteomics; Publishing; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Oncology; Radiation therapy; Radiology Specialty; Readiness; Resources; Science; Services; Systems Analysis; Techniques; Technology; Terrorism; Testing; Thinking; Time; Triage; United States National Institutes of Health; Work; biodosimetry; biological adaptation to stress; cancer care; cell killing; chemoradiation; citrin; coronavirus disease; drug-sensitive; experience; fractionated radiation; image guided radiation therapy; immunoregulation; in vivo; interest; mass casualty; medical countermeasure; metabolic abnormality assessment; metabolomics; molecular targeted therapies; mouse model; novel; point-of-care diagnostics; programs; resilience; response; targeted agent; targeted treatment; tissue injury; 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 enhanced immune response. 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, DU145 and LNCaP 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). The COVID disruption has impacted everyone. From my experience in disaster planning and response, I am involved with the scarce resources/crisis standards of care issues for the COVID19 pandemic including working with the Healthcare Resilience Task Force and PPE.

我们实验室项目的长期重点涉及辐射和微环境应激反应。我们现在专注于“辐射诱导的分子靶标”，即探索使用多分次（MF）辐射以及更高的单剂量（SD）来诱导细胞表型，使细胞对分子靶向治疗敏感。从本质上讲，放疗会使肿瘤增强药物杀伤增强免疫反应。该项目现已证明，不同剂量的辐射- MF和SD - （10 Gy x1, 2 Gy x5, 1 Gy x10和低至0.5 Gy x10）产生不同的表型。我们已经证明并发表了辐射后的细胞在短期内和60天后对至少一种药物更敏感，表明细胞适应。这篇文章现在已经发表了。诱导靶点的新观察对癌症适应分子靶向治疗和免疫治疗具有广泛的意义。我们目前正在研究靶点联合治疗和“合成致死率”。我们在诱导mRNA、miRNA、蛋白质和代谢组学变化的研究方面取得了重大进展。目前正在进行的项目包括研究PC3、DU145和LNCaP细胞的代谢组学变化、体内SD和MF以及表观遗传变化。我们现在正在与复杂系统分析方面的专家合作，以确定到达靶点的途径，并研究放射和药物的时机。由于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离有重要影响，包括直接和间接效应。通过最近成功的实验室审查，我们正在扩大合作，我们可以通过与RBB的Jim Mitchell和Deb Citrin或ROB以及RBB的Murali Cherukuri合作来检测适应性变化，他拥有超极化MRI技术来研究代谢适应，与这项工作密切相关的是正在努力确定辐射损伤的生物标志物。这与癌症有关，也与我在卫生与公众服务部（HHS）负责准备和应对的助理部长办公室的工作有关。我正在领导一个小组，为放射性和核恐怖主义以及其他事件制定民用医疗反应计划。这涉及到计划、政策和正常组织损伤相关的科学。通过NIAID在辐射医疗对策中心（CMCR）的支持，正在制定医疗对策。这一整体计划对美国的准备工作产生了重大影响，也对辐射造成的正常组织损伤以及暴露后缓解和治疗的潜力产生了附带影响。我们正在与其他机构（NIAID和国防部）合作，研究将这些缓解剂引入癌症治疗的潜力。美国国立卫生研究院和卫生与公众服务部的联系至关重要，它为医疗对策的发展和诊断带来了最新的科学思想。美国国立卫生研究院和卫生与公众服务部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。这是观察RNA在全身剂量范围内不同时间的表达，目前使用的是小鼠模型。鉴于核/辐射灾害的潜在规模，对潜在辐射伤亡进行准确的即时诊断的重要性再怎么估计也不为过。生物标志物的工作得到了NIAID和BARDA （of ASPR）的支持。COVID的中断影响了每个人。根据我在灾害规划和应对方面的经验，我参与了covid - 19大流行的稀缺资源/危机护理标准问题，包括与医疗保健复原力工作队和个人防护装备合作。