Neurobehavioral Core

项目总结：神经行为核心3 我们建议创建一个研究项目，题为“提高脑肿瘤的治疗指数 通过创新的FLASH放射治疗（FLASH-RT），专注于将一种新的放射疗法 快速进入临床。要检验的总体假设是， 剂量率（与当前临床实践中使用的低得多的剂量率相比）可以显著 改善正常组织并发症，同时保持可接受的（如果不是改善的）肿瘤控制。为了验证这一 假设，该计划将部署一系列全面的临床前研究，将严格评估 肿瘤控制、神经认知结果和FLASH-RT后对大脑的放射损伤， 常规剂量率辐照。总的来说，这些研究将产生必要的数据集， 将新型FLASH辐照平台快速转化为临床场景。小鼠临床前研究 评估原位肿瘤控制、认知、神经元和血管结构可塑性、免疫调节 放射损伤的氧依赖性机制与GBM犬患者的临床试验相结合， 告知肿瘤学家这种潜在的范式转变技术的潜在好处。目标 将通过剂量测定/物理学核心（核心2）开展的活动促进本计划项目的实施， 神经行为核心（核心3）。 Core 3的主要功能是提供一个统一的行为测试平台，其中动物 在其他性能地点（CHUV，斯坦福大学，印第安纳州）辐照的材料将运送到UCI并在UCI进行测试。的 UCI的神经行为核心能够适应动物所需的神经认知测试目标 进行单次和多次FLASH以及常规剂量率辐照方案， 在项目1、2和4中描述。这将通过统一的神经行为测试来实现 平台，旨在确定指定的辐射协议如何影响敏感的学习范式， 记忆和情绪，对治疗结果至关重要的多方面终点。 核心3将由Chares Limoli博士领导，他是分析多种辐射类型影响的著名专家， 范式和癌症治疗方案的认知，并由神经生物学家Munjal Acharya和 放射生物学家珍妮特·鲍奇该团队拥有超过12年的行为测试经验， 公认的一些第一个干细胞，外泌体，药理学和遗传学为基础的战略， 解决癌症治疗引起的认知功能障碍。总而言之，核心3将作为一个综合枢纽， 确保项目1、2和4的实验一致性。更广泛地说，核心3将提供一个主要的服务， 放射肿瘤学研究领域，促进相关数据的获取和传播， 放射肿瘤学和癌症治疗的潜在变革性分支。

PROJECT SUMMARY: NEUROBEHAVIORAL CORE 3 We are proposing the creation of a research program entitled, “Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT), focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is whether radiation delivered at ultra high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies that will critically evaluate tumor control, neurocognitive outcomes and resultant radiation injury to the brain following FLASH-RT and conventional dose rate irradiation. Collectively, these studies will generate the requisite data sets required for the rapid translation of the novel FLASH irradiation platform to the clinical scenario. Preclinical studies in mice assessing orthotopic tumor control, cognition, neuronal and vascular structural plasticity, immune-modulation and oxygen dependent mechanisms of radiation injury are coupled with a clinical trial in GBM dog patients to inform the oncologists of the potential benefits of this potentially paradigm shifting technology. The objectives of this program project will be facilitated by the activities conducted by the dosimetry/physics core (Core 2) and the Neurobehavioral Core (Core 3). The primary function of Core 3 will be to provide a uniform behavioral testing platform in which animals irradiated at the other performance sites (CHUV, Stanford, Indiana) will be shipped to and tested at UCI. The neurobehavioral core at UCI is able to accommodate the neurocognitive testing objectives required for animals subjected to single fraction, and multifraction FLASH and conventional dose rate irradiation protocols as described in Projects 1, 2 and 4. This will be accomplished through a unifying neurobehavioral testing platform, designed to determine how specified irradiation protocols impact sensitive paradigms of learning, memory and mood, multifaceted endpoints critical to therapeutic outcome. Core 3 will be led by Dr. Chares Limoli, renowned expert in analyzing the impact of multiple radiation types, paradigms and cancer treatment regimens on cognition, and operated by neurobiologist Munjal Acharya and radiobiologist Janet Baulch. This team has more than 12 years of behavioral testing experience and has been recognized for identifying some of the first stem cell, exosome, pharmacologic and genetic based strategies for resolving cancer treatment-induced cognitive dysfunction. In sum, Core 3 will serve as an integrative hub to ensure experimental consistency across Projects 1, 2 & 4. More broadly, Core 3 will provide a major service to the radiation oncology research field by promoting the acquisition and dissemination of data relevant to a potentially transformative branch of radiation oncology and cancer treatment in general.