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

细胞凋亡的发育调节作为儿科患者放疗引起的神经认知障碍的可改变驱动因素

• 批准号: 10371055
• 负责人: Kristopher Andrew Sarosiek
• 金额: $ 36.49万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371055
• 关键词: Adolescent; Adult; Affect; Aftercare; Age; Apoptosis; Apoptotic; Astrocytes; Automobile Driving; BAX gene; BCL2 gene; Biological Models; Birth; Blood Vessels; Blood capillaries; Brain; Brain region; Cancer Etiology; Cancer Survivor; Cancerous; Cell Cycle Arrest; Cell Death; Cells; Central Nervous System Neoplasms; Cephalic; Cessation of life; Chemotherapy and/or radiation; Child; Childhood; Childhood Central Nervous System Neoplasm; Childhood Malignant Brain Tumor; Clinical; Cognitive deficits; DNA; DNA Repair; Development; Diagnosis; Dose; Exhibits; Exposure to; External Beam Radiation Therapy; Family; Female; Future; Genetic; Goals; Growth; Homeostasis; Human; Hypersensitivity; Impairment; In Vitro; Inhibition of Apoptosis; Knock-out; Learning; Life; Life Experience; Long-Term Effects; Maintenance; Malignant neoplasm of central nervous system; Measures; Mediating; Memory; Microtubules; Modality; Morbidity - disease rate; Motor; Mus; Neonatal; Nervous system structure; Neurocognitive; Neurocognitive Deficit; Neurons; Normal Cell; Outer Mitochondrial Membrane; Pathway interactions; Patients; Pharmacology; Phenotype; Prevention; Protein Family; Proto-Oncogene Proteins c-myc; Quality of life; Radiation; Radiation therapy; Regulation; Reporting; Role; Severities; Shapes; Signal Pathway; Signal Transduction; Stimulus; Stress; Synaptic plasticity; TP53 gene; Testing; Thinness; Time; Tissues; Toxic effect; VDAC1 gene; Vascular Endothelial Cell; Visual Acuity; base; brain tissue; cancer cell; cancer prevention; cancer therapy; cell injury; cell type; chemotherapy; childhood cancer survivor; clinical application; conditional knockout; cytochrome c; dentate gyrus; improved; improved outcome; in vivo; innovation; male; medulloblastoma; member; mouse model; nerve stem cell; neurogenesis; neurosurgery; neurotoxicity; pediatric patients; postnatal; prevent; response; senescence; stem cells; tool; treatment strategy; tumor; tumorigenesis

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.

抽象的 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。 CNS 肿瘤，包括最常见的亚型 - 髓母细胞瘤，通常用外束治疗 放射疗法（XRT）以及神经外科和化学疗法以及这些治疗的改善 在过去的四十年中，模式增加了生存率和治愈率。但是，一半以上的小儿 用XRT经验改变生活的神经认知障碍（NI）的患者，尤其是 在年轻时被诊断出的儿童中很突出。实际上，幼儿通常在 XRT XRT的学习，记忆，执行处理，视力和精细的运动协调能力更高 比率比接受类似剂量治疗的成年人更严重。尽管显而易见 最大化儿童时期的治疗后生活质量癌症的生存，我们对 驱动XRT诱导的神经毒性的机制有限，目前没有临床使用的缓解剂。 凋亡（程序性细胞死亡）是一种进化保存的细胞死亡途径，对于正常 发育，组织稳态维持和预防癌症。该途径经过精心控制 由Bcl-2家族的蛋白质家族，其中包含促凋亡的和亲源的成员 对凋亡细胞死亡的承诺。大多数抗癌疗法在癌细胞或正常细胞中诱导凋亡 通过损害键的细胞组件，例如DNA或微管，或通过阻止钥匙信号通路。我们 已经发现，在产后生活中，在健康组织中细胞凋亡受到动态调节。这个法规 响应损害或压力来驱动细胞脂肪决策，并为为什么许多孩子提供解释 发展认知可以定义癌症治疗。此外，我们发现发展脑组织可能是 通过阻断Bax介导的细胞凋亡，免受与治疗相关的凋亡的保护。但是，还不清楚 发育中的大脑中的哪些细胞最有可能在钥匙处经历辐射诱导的凋亡 发育时间点以及每种细胞类型的丧失如何促进长期神经认知后遗症。 在此提案中，我们将1）比较XRT在神经元内的单细胞水平上诱导的细胞命运 新生儿，少年和成年小鼠大脑中的血管内皮细胞，并确定其在 XRT诱导的Ni和2）评估通过阻塞降低或消除XRT诱导的神经毒性的潜力 遗传或药物凋亡（通过上游调节剂）和凋亡的长期影响 抑制。这些研究将为XRT诱导的神经毒性领域带来急需的清晰度，并放置 未来临床应用的基础工作，可以有意义地改善小儿脑癌的生活 幸存者及其家人。