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

放射性脑坏死细胞机制的表征用于临床干预

基本信息

批准号：
10273297
负责人：
DAVID R GROSSHANS
金额：
$ 17.49万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2021-08-02 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273297
关键词：
3-Dimensional Adult Adverse effects Animal Model Animals Apoptosis Area Biological Biological Factors Biological Markers Brain Brain Injuries Brain Neoplasms Cancerous Cell Death Cells Cerebrum Cessation of life Characteristics Childhood Childhood Ependymoma Clinical Clinical Data Coculture Techniques Cognitive Cognitive deficits Cranial Irradiation Data Dependence Disease model Distal Dose Educational workshop Effectiveness Engineering Exposure to Glioma Human Image In Vitro Incidence Inflammatory Intensity modulated proton therapy Intervention Knowledge Laboratories Laboratory Study Lead Life Linear Energy Transfer Link Magnetic Resonance Imaging Malignant Childhood Neoplasm Mission Modality Modeling Molecular National Cancer Institute Necrosis Necrosis Induction Normal tissue morphology Organoids Outcome Paralysed Pathway interactions Patients Pharmacology Photons Planning Techniques Preparation Prevention Process Protons Public Health Radiation Radiation Injuries Radiation necrosis Radiation therapy Relative Biological Effectiveness Research Research Support Rodent Roentgen Rays Role Scanning Signal Transduction Survivors Techniques Tissues Transgenic Animals Treatment Side Effects Uncertainty brain cell brain tissue cancer cell cancer rehabilitation cancer therapy cell injury cell type clinical investigation clinical practice clinically relevant combat design disorder control high risk imaging platform improved in vivo in vivo Model induced pluripotent stem cell insight irradiation medulloblastoma novel pediatric patients pre-clinical predictive modeling proton beam proton therapy radiation effect radiation response radiation risk response side effect treatment planning treatment response tumor

项目摘要

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.

项目摘要/摘要童年癌症的治疗率有所提高。不幸的是，许多潮流现在生活在终身治疗本身的影响。用于脑肿瘤的放射治疗尤其有害。最多严重的副作用是坏死，可能导致无力，瘫痪甚至死亡。质子疗法是日益流行的辐射方式。质子治疗减少了暴露于正常组织和Reby 可能会减少辐射后认知定义的事件。但是，最近的研究，包括我们的自己表明，某些质子梁的某些区域可能比其他区域更损害脑组织可能导致更高的坏死率。在这里，我们将开发高精度模型以关联与质子束的物理参数的坏死。这些模型将包括多细胞类型的人大脑“器官”和啮齿动物模型。使用这些模型以及临床数据，我们将确定可能导致坏死的质子治疗的物理因素。这很重要，因为这些数据可用于设计更安全的质子治疗疗法，其中生物学上最有效的部分梁仅放置在肿瘤内。这应该减少坏死并改善疾病控制。在我们研究的第二个组成部分，我们将检查坏死的分子机制。而不是简单无组织的死亡，我们将确定辐射是否诱发有序编程的细胞死亡路径。我们将实现以下目标；（1）将质子束的物理因子与生物学联系起来反应，（2）探索辐射引起的脑损伤的细胞和分子机制，（3）验证质子束有效性变异性的临床后果。知识获得了将迅速影响脑肿瘤患者的治疗，并加快药剂的临床引入和打击辐射对大脑的负面影响的方法。