(PQ9) Directed and unbiased studies of synaptic injuries as sequelae of radiotherapy: mapping, sex-dependence, and reversal

(PQ9) 作为放射治疗后遗症的突触损伤的定向和公正研究：定位、性别依赖性和逆转

• 批准号: 9754627
• 负责人: JOSEPH G DUMAN
• 金额: $ 50.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754627
• 关键词: 3-Dimensional; Acute; Address; Adult; Affect; Age; Animal Model; Area; Atlases; Behavioral; Biological Assay; Brain; Brain Injuries; Brain Neoplasms; Brain region; Cancer Etiology; Cancer Patient; Cancer Survivor; Caregivers; Cells; Cessation of life; Chemosensitization; Child; Clinical; Cognition; Cognitive; Cognitive deficits; Complement; Cranial Irradiation; Data; Data Quality; Defect; Dependence; Development; Diagnosis; Dose; Excitatory Synapse; Exhibits; Female; Fluorescent Probes; Future; Goals; Health; Hippocampus (Brain); Imaging Techniques; Impaired cognition; Individual; Inflammatory; Injury; Intervention; Investigation; Knowledge; Lead; Light; Literature; Malignant Childhood Neoplasm; Malignant neoplasm of brain; Maps; Mediating; Modality; Modeling; Molecular; Morphology; Mus; Nature; Neurocognitive; Neurocognitive Deficit; Neurons; Outcome; Pathologic; Patients; Predisposition; Prevention; Prosencephalon; Protocols documentation; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation therapy; Recovery; Research; Signal Transduction; Site; Societies; Structure; Survival Rate; Symptoms; Synapses; Techniques; Testing; Therapeutic; Time; Translating; Translations; Traumatic Brain Injury; age difference; age group; anticancer treatment; brain dysfunction; cancer therapy; cell injury; clinical application; clinically relevant; cognitive function; cohort; combat; dentate gyrus; excitatory neuron; experience; glutamatergic signaling; in vivo; interdisciplinary approach; male; multidisciplinary; nerve stem cell; neural circuit; neurogenesis; neuronal circuitry; novel; novel strategies; postnatal; prevent; radiation effect; radiation response; radioresistant; relating to nervous system; response; sex; synaptogenesis; theories; therapy design; tool

Abstract Brain cancer is a terrifying diagnosis representing a relatively large segment of childhood cancer, yet thanks to great advances in treatment, survival rates among children now exceed 80%. These positive clinical outcomes require the use of radiotherapy (RT), but like other treatment modalities, RT causes significant long- term neurocognitive sequelae impacting not only cancer survivors, but also their caregiver networks and society. Adults receiving RT for brain cancers also suffer similar symptoms and would benefit from the amelioration or elimination of the neurocognitive effects of RT. In theory, RT-induced brain injury is easier to treat than other brain injuries, given that the time of injury is known and pretreatment is feasible. However, the unclear nature of RT-induced brain damage is a major obstacle to doing so. Research on RT-induced brain injury has focused on the dividing neuroprogenitor (NP) cells from which a small pool of postnatal, “adult- born” neurons arises in the dentate gyrus, as the hippocampus (of which the dentate gyrus is part) is particularly sensitive to radiation. Certainly, NP cell damage contributes to RT-induced sequelae. However, we and others have recently shown that terminally differentiated neurons, long thought to be resistant to radiation, undergo synaptic alterations in response to radiation. This observation has major implications for the treatment of RT-induced sequelae because it suggests that the damage could happen throughout the entire brain and not be limited to the small, discrete sites of postnatal neuron formation. In this proposal, we present our most recent data on this phenomenon, showing that therapeutic doses of radiation lead to ectopic synaptogenesis and synapse potentiation within 1 hr of RT. Females are more affected than males by this insult, and suppressing glutamate signaling prevents both synapse expansion and subsequent long-term synapse loss. Many questions remain unanswered, however: How localized is the injury? Does the injury promulgate along neuronal circuits? Are some regions of the brain more or less susceptible to the injury? How are these parameters affected by the sex of the individual undergoing RT? Can RT-mediated synaptic defects be reversed? These are critical questions whose answers are required to rationally design therapies to combat RT-induced neurocognitive sequelae. We propose to define the nature of acute RT-induced synaptic damage at by (i) creating at atlas of RT-mediated synaptic injury in the mouse brain using fluorescent probes for neuronal activity and synaptic potentiation, advanced imaging techniques and multidimensional analysis, (ii) testing the influences of age and sex on subject response to RT, and (iii) manipulating cellular signaling to attempt to reverse RT-mediated synaptic damage. We propose a novel and multidisciplinary approach to dissecting the nature of RT-mediated synaptic damage at the molecular, synaptic, cellular, and organismal, i.e. behavioral, levels. The results of this translation proposal have the potential to greatly and positively impact the health of cancer survivors of all ages, and our techniques could be used to investigate other types of brain injuries.

抽象的 脑癌是一种可怕的诊断，代表了儿童癌症中相对较大的一部分，但 由于治疗方面的巨大进步，儿童的存活率现已超过 80%。这些积极的临床 治疗结果需要使用放射治疗 (RT)，但与其他治疗方式一样，放射治疗会导致显着的长期 术语神经认知后遗症不仅影响癌症幸存者，还影响他们的护理人员网络和 社会。接受脑癌放疗的成年人也会出现类似的症状，并且会受益于 改善或消除放疗对神经认知的影响。理论上，放疗引起的脑损伤更容易 与其他脑损伤相比，考虑到损伤时间已知并且预处理是可行的。然而， 放疗引起的脑损伤的性质尚不清楚，这是实现这一目标的主要障碍。 RT诱导大脑研究 损伤集中在分裂的神经祖细胞（NP）上，其中一小部分出生后的“成人- “天生的”神经元出现在齿状回中，因为海马体（齿状回是海马体的一部分） 对辐射特别敏感。当然，NP 细胞损伤会导致 RT 引起的后遗症。然而， 我们和其他人最近表明，长期以来被认为具有抵抗力的终末分化神经元 辐射，因辐射而发生突触改变。这一观察结果具有重大意义 放疗引起的后遗症的治疗，因为它表明损害可能发生在整个过程中 大脑，并且不限于出生后神经元形成的小而离散的部位。在本提案中，我们提出 我们关于这一现象的最新数据表明，治疗剂量的辐射会导致异位 RT 1 小时内突触发生和突触增强。女性比男性受此影响更大 侮辱，抑制谷氨酸信号传导可以防止突触扩张和随后的长期 突触损失。然而，许多问题仍未得到解答：损伤的局部性如何？有没有受伤 沿着神经元回路传播？大脑的某些区域是否更容易或不太容易受到伤害？如何 这些参数是否受到接受 RT 的个体性别的影响？ RT 介导的突触缺陷可以吗 被逆转？这些都是关键问题，需要回答这些问题才能合理设计治疗方法来对抗 放疗引起的神经认知后遗症。我们建议定义急性放疗引起的突触损伤的性质 (i) 使用神经元荧光探针在小鼠大脑中创建 RT 介导的突触损伤图集 活动和突触增强、先进的成像技术和多维分析，(ii) 测试 年龄和性别对受试者对 RT 反应的影响，以及 (iii) 操纵细胞信号传导以尝试 逆转 RT 介导的突触损伤。我们提出了一种新颖的多学科方法来剖析 RT 介导的分子、突触、细胞和有机体突触损伤的性质，即行为、 水平。该翻译提案的结果有可能对人类健康产生巨大而积极的影响 所有年龄段的癌症幸存者，我们的技术可用于研究其他类型的脑损伤。