IMAGING BIOMARKERS FOR RADIATION-INDUCED NECROSIS

描述（由申请人提供）：放射性坏死是一种严重但迟发的正常组织损伤类型，可能导致放射治疗后脑肿瘤患者管理面临重大挑战。放射性坏死会导致局限性神经系统后遗症，限制患者的生活质量。放射性坏死的定量识别和分期方法在神经肿瘤学领域具有重要意义。此外，识别可以降低放射性坏死的发生率或严重程度的神经保护剂和可以减轻症状的治疗剂将对患者护理产生显著的积极影响。对非侵入性定量表征方法的需求是诊断脑中组织辐射损伤的特别挑战。这一提议为满足这一关键需求提供了重要的进展。磁共振成像（MRI）可以通过测量对重要生理和细胞参数敏感的参数（包括细胞密度、脑血容量和流量、氧利用率和血管渗透性或渗漏）来提供非侵入性表征。详细了解影响放射性坏死的发生和进展的因素，需要开发强大的动物模型，使组织损伤的组织学（细胞）在照射的大脑中的清晰描述。本申请的目的是开发一种良好表征的放射性坏死小鼠模型，以验证用于识别该模型中坏死的非侵入性、可平移MRI工具，并随后研究通过治疗干预预防或减轻该组织损伤的机制。更具体地说，赠款的目的是：1）优化最近开发的脑辐射坏死小鼠模型; 2）开发和验证可以唯一识别辐射坏死的MRI标记物; 3）测试推定的神经保护剂或治疗化合物，并通过非侵入性MR成像技术监测其减少辐射损伤的功效。该项目将利用一些尖端的实验技术，包括高场强小动物MRI设备和先进的成像序列。将使用Leksell伽玛刀Perfectomy装置（一种用于良性和恶性脑肿瘤患者立体定向照射的最先进装置）对小鼠进行照射，在建立放射性坏死后，将测试用于预防和减轻组织损伤的新型介入机制。这一系列的实验将使我们对脑照射后脑组织的变化有更清楚的了解。非侵入性监测这些变化的能力，以及通过治疗干预预防和减轻这些变化的能力，将导致更好的临床结果和改善脑肿瘤患者的生活质量，其治疗范例包括放射治疗。 公共卫生相关性：放射治疗引起的组织损伤（坏死）会严重影响脑肿瘤患者的生活质量。本申请描述了磁共振成像（MRI）方法的发展，以更好地表征和分期辐射坏死。非侵入性监测放射性坏死的能力，以及通过治疗干预预防和减轻放射性坏死的能力，将为治疗范例包括放射治疗的脑肿瘤患者带来更好的临床结局和改善的生活质量。

DESCRIPTION (provided by applicant): Radiation necrosis is a severe, but late occurring, type of injury to normal tissue that can lead to significant challenges in the management of brain-tumor patients following radiation therapy. Radiation necrosis causes focal neurological sequelae that limit patients' quality of life. Quantitative methods to identify and stage radiation necrosis are of paramount importance in the neuro-oncology community. Additionally, the identification of neuroprotectants that could reduce the incidence or severity of radiation necrosis and therapeutics that could mitigate symptoms would have significant positive impact on patient care. The need for non-invasive, quantitative characterization methods is a particular challenge for diagnosing tissue radiation- damage in the brain. This proposal offers an important advance to meet this critical need. Magnetic resonance imaging (MRI) can provide non-invasive characterization, through measurement of parameters that are sensitive to important physiologic and cellular parameters, including cell density, cerebral blood volume and flow, oxygen utilization, and vascular permeability or leakiness. A detailed understanding of the factors that affect the onset and progression of radiation necrosis requires the development of robust animal models that enable a clear histologic (cellular) description of tissue damage in the irradiated brain. The goals of this application are to develop a well-characterized mouse model of radiation necrosis, to validate non-invasive, translatable MRI tools for identifying necrosis in this model, and subsequently to investigate mechanisms by which this tissue damage can be prevented or mitigated through therapeutic interventions. More specifically, the aims of the grant to: 1) optimize a recently developed mouse model of radiation necrosis in brain; 2) develop and validate MRI markers that can uniquely identify radiation necrosis; 3) test putative neuroprotectant or therapeutic compounds and monitor their efficacy in reducing radiation damage by non-invasive MR imaging techniques. The project will make use of a number of cutting-edge experimental techniques including high field strength small-animal MRI equipment and advanced imaging sequences. Mice will be irradiated using the Leksell Gamma Knife Perfexion unit, a state-of-the-art unit used for stereotactic irradiation of patients with benign and malignant brain tumors, and following the establishment of radiation necrosis, novel interventional mechanisms will be tested for the prevention and mitigation of tissue damage. This series of experiments will result in a significantly clearer understanding of the brain tissue changes that follow cranial irradiation. The ability to monitor these changes non-invasively, and to prevent and mitigate these changes with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors whose treatment paradigms include radiation therapy. PUBLIC HEALTH RELEVANCE: Tissue damage (necrosis) caused by radiation treatment can seriously affect the quality of life of brain-tumor patients. This application describes the development of magnetic resonance imaging (MRI) methods to better characterize and stage radiation necrosis. The ability to monitor radiation necrosis non-invasively, and to prevent and mitigate it with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors whose treatment paradigms include radiation therapy.