Radiation-induced molecular targets

我们实验室计划的长期重点涉及辐射和微环境应激反应。我们现在专注于“辐射诱导的分子靶点”，即探索使用多分割（MF）辐射以及更高的单剂量（SD）诱导细胞表型，使细胞对分子靶向治疗敏感。从本质上讲，辐射将使肿瘤增强药物杀伤力。该项目现已证明，不同剂量的辐射- MF和SD -（10戈伊x1、2戈伊x5、1戈伊x10和低至0.5戈伊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对至少一种药物更敏感，并且在60天后对一种药物更敏感，这表明细胞适应。这份报告现已出版。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。我们现在正在研究靶点的联合治疗和“合成致死”，我们在研究可诱导的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组学变化、PC 3细胞的体内SD和MF以及表观遗传变化。我们现在正在与复杂系统分析专家合作，以确定靶向途径，并研究辐射和药物的时机。由于对免疫调节的主要兴趣，我们的工作对辐射的剂量和分级具有重要影响，可用于增强免疫以控制肿瘤，包括直接和远距离效应。随着最近成功的实验室审查，我们正在扩大合作，通过这种合作，我们可能会检测到适应性变化，与RBB的Jim Mitchell和Deb Citrin或ROB和Murali Cherukuri合作，他们拥有超极化MRI技术来研究代谢适应。这与癌症有关，也与我在卫生与公众服务部（HHS）准备和反应助理部长办公室所做的工作有关。我正在领导一个小组，为放射性和核恐怖主义及其他事件制定民用医疗应急计划。这涉及规划，政策和正常组织损伤相关的科学。目前正在通过NIAID的支助，在防辐射医疗对策中心制定医疗对策。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副作用。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护理的可能性。NCI- HHS联系的至关重要性是为医学对策开发和诊断带来最新的科学思想-NIH和DHHS计划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不同时间的RNA表达，目前使用小鼠模型。鉴于核/放射性灾难的潜在规模，对用于对潜在辐射伤亡进行分类的精确的护理点诊断的重要性无论如何估计都不过分。生物标志物工作得到了NIAID和巴尔达（ASPR）的支持。

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).