Characterization of the cellular mechanisms of radiation induced brain necrosis for clinical intervention

项目概要/摘要 儿童癌症的治愈率有所提高。不幸的是，许多幸存者现在生活与终身的一面 治疗本身的影响。放射治疗，用于脑肿瘤，是特别有害的。最 严重的副作用是坏死，可导致虚弱、瘫痪甚至死亡。质子治疗是一种 越来越流行的放射疗法质子治疗减少了对正常组织的暴露， 可以降低辐射后认知缺陷的发生率。然而，最近的研究，包括我们 他自己的研究表明，质子束的某些区域对脑组织的损害可能比其他区域更大 可能导致更高的坏死率。在这里，我们将开发高精度模型来关联 质子束物理参数造成的坏死这些模型将包括多细胞类型的人类 脑“类器官”以及啮齿动物模型。使用这些模型以及临床数据，我们将 确定质子治疗可能导致坏死的物理因素。这一数据的重要性在于， 可用于设计更安全的质子治疗，其中， 光束仅放置在肿瘤内。这将减少坏死并改善疾病控制。中 我们研究的第二个组成部分，我们将研究坏死的分子机制。而不是 简单的无序死亡，我们将确定辐射是否会诱导有序的程序性细胞死亡 通路我们将进行以下工作：（1）将质子束的物理因素与生物学特性联系起来 反应，（2）探索放射性脑损伤的细胞和分子机制，（3） 验证质子束有效性变化的临床后果。获得的知识 将迅速影响脑肿瘤患者的治疗，并加快药物的临床引入， 以及对抗辐射对大脑的负面影响的方法。

Project Summary/Abstract Cure rates for childhood cancers have improved. Unfortunately, many survivors now live with life-long side effects from treatment itself. Radiation therapy, used for brain tumors, is particularly damaging. The most serious side effect is necrosis which can result in weakness, paralysis or even death. Proton therapy is an increasingly popular radiation modality. Proton therapy reduces exposure to normal tissues and the reby may decrease the incidence of cognitive deficits following radiation. However, recent studies, including our own suggest that certain areas of proton beams may be more damaging to brain tissue than others potentially leading to higher rates of necrosis. Here we will develop high accuracy models to correlate necrosis with the physical parameters of proton beams. These models will include multi-cell type human brain “organoids” as well as rodent animal models. Using these models as well as clinical data, we will identify the physical factors of proton therapy which may lead to necrosis. This is significant in that this data may be used to design safer proton therapy treatments in which the most biologically effective portions of beams are solely placed within the tumor. This should reduce necrosis and improve disease control. In a second component of our study, we will examine the molecular mechanisms of necrosis. Rather than being simple dis-organized death, we will determine if radiation induces an orderly programmed cell death pathway. We will conduct the following aims; (1) relate the physical factors of proton beams with biological response, (2) explore the cellular and molecular mechanisms of radiation induced brain damage and (3) validate the clinical consequences of variability in the effectiveness of proton beams. The knowledge gained will quickly influence the treatment of brain tumor patients and expedite the clinical introduction of agents and approaches to combat the negative effects of radiation on the brain.