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：
10460578
负责人：
DAVID R GROSSHANS
金额：
$ 17.14万
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/10460578
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 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 Reverse engineering 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.

项目概要/摘要不幸的是，儿童癌症的治愈率有所提高，许多幸存者现在仍患有终身癌症。用于脑肿瘤的放射治疗的影响尤其严重。质子治疗的严重副作用是坏死，可能导致虚弱、瘫痪甚至死亡。越来越流行的质子治疗减少了对正常组织的暴露和辐射。可能会降低辐射后认知缺陷的发生率但是，最近的研究，包括我们的研究。自己认为质子束的某些区域可能比其他区域对脑组织的损害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。这些模型将包括多细胞类型的人类坏死与质子束的物理参数。利用这些模型和临床数据，我们将研究大脑“类器官”以及啮齿动物模型。确定质子治疗可能导致坏死的物理因素这一数据的意义重大。可用于设计更安全的质子治疗，其中最具生物学效果的部分光束仅放置在肿瘤内，这应该可以减少坏死并改善疾病控制。我们研究的第二个组成部分，我们将研究坏死的分子机制。简单的无组织性死亡，我们将确定辐射是否会诱导有序的程序性细胞死亡我们将实现以下目标：（1）将质子束的物理因素与生物联系起来。反应，(2) 探索辐射引起的脑损伤的细胞和分子机制，以及 (3) 验证质子束有效性变异的临床后果。将迅速影响脑肿瘤患者的治疗并加速药物的临床引入以及对抗辐射对大脑负面影响的方法。