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

摘要/概要 国家癌症研究所，挑衅性问题倡议认为，具体的高影响力的问题， 癌症研究，包括什么是发展的分子和/或细胞机制， 癌症治疗是否会导致严重的不良后遗症？认知减退，包括学习障碍， 对于近50万不同年龄段的美国人来说， 放射治疗脑癌。最近，已经观察到树枝状形态的变化 海马和内侧前额叶皮层中的低到中等剂量的X射线和充电后， 代表肿瘤边缘患者剂量（1 - 10戈伊）的粒子（质子和较重离子）。 由此产生的形态缺陷已被证明是暂时符合受损的行为 在多种啮齿动物模型中使用各种认知测试来评估性能。传统的生物物理学模型 在理解剂量输送和辐射中正常组织效应最小化方面发挥了关键作用 治疗;然而，这种模型尚未被考虑用于包括各种结构的复杂结构。 大脑中的神经元类型我们的提案汇集了内华达州拉斯维加斯大学的建模技能 拉斯维加斯和实验室在加州，欧文大学开发一个预测随机 辐射诱导齿状回颗粒细胞层树突形态变化的微剂量学模型 (GCL)和锥体细胞（PYC）神经元在海马和内侧前额叶皮质的转基因小鼠 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（IR）可改变海马、内侧前额叶皮质和海马神经元的树突形态 （mPFC），以及其他大脑区域中可能的神经元，生物物理学模型基于随机 微剂量测定法可以导致对不同辐射剂量、形态 （放射类型）和递送范例（急性与分次）。此外，我们假设年龄相关 敏感性将影响CNS的剂量和时间依赖性辐射反应， 在剂量分次后，变化将是响应性的（即改善）。我们的机械模型将提供一个 树突形态学和棘动力学变化的定量描述取决于剂量， 使用X射线、质子和碳束的剂量分级范例， 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 剂量依赖性放射性树突状形态学参数，将通过以下方法直接进行实验检测： 在研究时，使年轻（1个月）和成年（6个月）小鼠接受仔细选择的照射模式， 随着时间的推移（30天或更长时间）产生的形态学变化。

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).