Developmental regulation of apoptosis as a modifiable driver of radiotherapy-induced neurocognitive impairment in pediatric patients

摘要 中枢神经系统(CNS)肿瘤是儿童癌症死亡和发病率的主要原因。氯化萘 肿瘤，包括最常见的亚型髓母细胞瘤，常规采用外照射治疗。 放射治疗(XRT)以及神经外科手术和化疗，以及这些治疗的改进 在过去的40年里，治疗方式提高了存活率和治愈率。然而，超过一半的儿科医生 接受XRT治疗的患者经历了改变生活的神经认知障碍(NI)，尤其是 在幼年确诊的儿童中表现突出。事实上，年幼的儿童通常在 XRT后学习、记忆、执行加工、视觉敏锐度和精细运动协调能力大大提高 与接受类似剂量治疗的成年人相比，其发病率和严重性更高。尽管显然重要的是 为了最大限度地提高儿童中枢神经系统癌症幸存者的治疗后生活质量，我们对 驱动XRT诱导的神经毒性的机制是有限的，目前还不存在临床上有用的缓释剂。 细胞凋亡(程序性细胞死亡)是一种进化保守的细胞死亡途径，对正常细胞至关重要 发展、维持组织动态平衡和预防癌症。这条路是经过精心控制的 通过bcl2蛋白家族，该家族包含促凋亡和促生存成员，控制着 致力于细胞凋亡性死亡。大多数抗癌治疗会诱导癌细胞或正常细胞发生凋亡。 通过破坏关键的细胞成分，如DNA或微管，或通过阻断关键的信号通路。我们 已经发现，在出生后的生命中，健康组织中的细胞凋亡是动态调节的。这项规定 决定细胞命运以应对损伤或压力，并解释了为什么许多孩子 因癌症治疗而出现认知缺陷。此外，我们发现，发育中的脑组织可以 通过阻断Bax介导的细胞凋亡来防止治疗相关的细胞凋亡。然而，目前还不清楚 发育中的大脑中的哪些细胞最有可能在关键时刻经历辐射诱导的细胞凋亡 发育时间点，以及每种细胞类型的丧失如何导致长期的神经认知后遗症。 在这个方案中，我们将1)在神经元、神经胶质细胞内的单个细胞水平上比较XRT诱导的细胞命运 以及新生、幼年和成年小鼠脑内的血管内皮细胞，并确定它们在 XRT诱导的NI和2)评估通过阻断减少或消除XRT诱导的神经毒性的可能性 基因或药物上的细胞凋亡(通过上游调节)和细胞凋亡的长期影响 抑制力。这些研究将为XRT诱导的神经毒性领域带来亟需的澄清，并为 为未来的临床应用奠定基础，有意义地改善儿童脑癌的生活 幸存者和他们的家人。

ABSTRACT Central nervous system (CNS) tumors are a leading cause of cancer death and morbidity in children. CNS tumors, including the most common subtype – medulloblastomas, are routinely treated with external beam radiation therapy (xRT) as well as neurosurgery and chemotherapy, and improvements in these treatment modalities have increased survival and cure rates over the last four decades. However, over half of the pediatric patients treated with xRT experience life-altering neurocognitive impairment (NI), which is especially prominent in children diagnosed at a young age. In fact, young children commonly exhibit impairments in learning, memory, executive processing, visual acuity and fine motor coordination post xRT at vastly higher rates and with more severity than adults treated with similar doses. Despite the clear importance of maximizing post-treatment quality of life for childhood CNS cancer survivors, our understanding of the mechanisms driving xRT-induced neurotoxicity is limited and no clinically-useful mitigators currently exist. Apoptosis (programmed cell death) is an evolutionarily-conserved cell death pathway that is critical for normal development, maintenance of tissue homeostasis, and cancer prevention. This pathway is carefully controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that control the commitment to apoptotic cell death. Most anti-cancer therapies induce apoptosis in cancerous or normal cells by damaging key cellular components such as DNA or microtubules or by blocking key signaling pathways. We have found that apoptosis is dynamically regulated in healthy tissues during postnatal life. This regulation drives cell fate decisions in response to damage or stress and provides an explanation for why many children develop cognitive deficits from cancer treatments. In addition, we found that developing brain tissue can be protected from treatment-associated apoptosis by blocking BAX-mediated apoptosis. However, it is unclear which cells within the developing brain are most likely to undergo radiation-induced apoptosis at key developmental time points and how the loss of each cell type contributes to long-term neurocognitive sequelae. Within this proposal, we will 1) compare cell fates induced by xRT at the single cell level within neuronal, glial and vascular endothelial cells within the neonatal, juvenile and adult mouse brain and establish their role in xRT-induced NI and 2) evaluate the potential to reduce or eliminate xRT-induced neurotoxicity by blocking apoptosis genetically or pharmacologically (via upstream regulators) and the long-term effects of apoptosis inhibition. These studies will bring much-needed clarity to the field of xRT-induced neurotoxicity and lay the groundwork for future clinical applications that meaningfully improves the lives of pediatric brain cancer survivors and their families.