(9) Biophysical Description of Age and Dose Dependent Changes to Dendritic Morphology that Impact Cognition following Radiation Cancer Therapy

摘要/摘要 国家癌症研究所，挑衅性问题倡议考虑特定的高影响问题 癌症研究，包括导致癌症发生的分子和/或细胞机制是什么 癌症治疗引发了严重的不良后遗症？认知功能减退，包括学习障碍和 对于近50万不同年龄的美国人来说，记忆是常见的 每年对脑癌患者进行放射治疗。最近观察到树枝状形态的变化。 在低到中等剂量的X射线和带电照射后的海马区和内侧前额叶皮质 代表肿瘤边缘患者剂量的粒子(质子和重离子)(1至10GY)。 由此产生的形态缺陷与行为障碍在时间上是一致的。 在多种啮齿动物模型中使用各种认知测试的表现。传统上，生物物理模型有 在理解辐射中的剂量传递和最小化正常组织效应方面发挥了关键作用 治疗；然而，这种模型还没有被考虑用于由各种不同的 大脑中神经元的类型。我们的提案结合了内华达大学拉斯维加斯分校的建模技能 拉斯维加斯和加州大学欧文分校的实验室共同开发了一种预测性随机 辐射诱发齿状颗粒细胞层树突形态改变的微剂量学模型 转基因小鼠海马区和内侧前额叶皮质的GCL和PYC神经元 使用高度创新的计算-实验相结合的方法。我们的主要假设是 电离辐射将改变海马区、内侧前额叶皮质神经元的树突形态 (MPFC)，以及其他脑区可能的神经元，以及基于随机的 微剂量学可以准确预测不同辐射剂量、模式下的这些变化。 (放射型)和分娩模式(急性型与分化型)。此外，我们假设与年龄有关的 敏感度将影响中枢神经系统的剂量和时间依赖的辐射响应，并且这些 在剂量分级后，变化将是响应的(即改善的)。我们的机械模型将提供 定量描述树突形态和脊柱动力学随剂量和剂量的变化 使用x射线、质子和碳束的剂量分级范例，使用的首选辐射方式 用于脑癌的临床治疗。此外，生物物理模型将包括年龄、时间和 将通过实验直接测试的与剂量相关的放射性树枝状形态参数 在研究的同时，让幼鼠(1个月)和成年鼠(6个月)接受精心选择的照射范例 由此产生的形态变化随着时间的推移(30天或更长时间)。

Abstract/Summary The National Cancer Institute, Provocative Question Initiative considers specific high impact questions in cancer research, including what are the molecular and/or cellular mechanisms that underlie the development of cancer therapy induced severe adverse sequelae? Cognitive decrements including impaired learning and memory are common occurrences for the nearly one-half a million Americans of varying ages undergoing radiation therapy for brain cancers each year. Recently, changes to dendritic morphology have been observed in the hippocampus and medial pre-frontal cortex following low to moderate doses of x-rays and charged particles (protons and heavier ions) that are representative of patient doses at the tumor margins (1 to 10 Gy). The resultant morphological deficits have been shown to be temporally coincident with impaired behavioral performance using a variety of cognitive tests in multiple rodent models. Traditionally biophysics models have played a key role in understanding dose delivery and the minimization of normal tissue effects in radiation therapy; however such models have not been considered for the complex structures that comprise various types of neurons in the brain. Our proposal brings together the modeling skills at the University of Nevada, Las Vegas and the laboratory at the University of California, Irvine to develop a predictive stochastic microdosimetric model of radiation induced changes to dendritic morphology in dentate granule cell layer (GCL) and pyramidal cell (PYC) neurons in the hippocampal and medial pre-frontal cortex of transgenic mice using a highly innovative combined computational-experimental approach. Our primary hypothesis is that ionizing radiation (IR) will alter dendritic morphology in neurons of the hippocampus, medial pre-frontal cortex (mPFC), and likely neurons in other brain areas and that biophysics models based on a stochastic microdosimetry can lead to accurate predictions of these changes for different radiation doses, modalities (radiation type) and delivery paradigms (acute vs fractionated). Furthermore, we hypothesize that age related susceptibility will influence the dose and time-dependent radiation response of the CNS, and that these changes will be responsive (i.e. ameliorated) after dose fractionation. Our mechanistic model will provide a quantitative description of changes to dendritic morphology and spine dynamics as dependent on dose and dose fractionation paradigms using x-rays, protons, and carbon beams, the preferred radiation modalities used for the clinical management of brain cancer. In addition, biophysical models will incorporate age, time and dose-dependent radio-dendritic morphology parameters that will be directly tested experimentally, by subjecting young (1 month) and adult (6 month) mice to carefully selected irradiation paradigms, while studying the resulting morphologic changes over time (30 days or longer).