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: 10561668
• 负责人: Kristopher Andrew Sarosiek
• 金额: $ 35.76万
• 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/10561668
• 关键词: Adolescent; Adult; Affect; Aftercare; Age; Apoptosis; Apoptotic; Astrocytes; Automobile Driving; BAX gene; BCL1 Oncogene; Bax protein; Biological Models; Birth; Blood Vessels; Blood capillaries; Brain; Brain region; Cancer Etiology; Cancer Survivor; Cancerous; Caspase; Cell Cycle Arrest; Cell Death; Cell Survival; 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; Impairment; In Vitro; Induction of Apoptosis; 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; Neurocognitive; Neurocognitive Deficit; Neurons; Normal Cell; Outer Mitochondrial Membrane; Pathway interactions; Patients; Permeability; 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; 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; neural; neurogenesis; neuroprotection; neurosurgery; neurotoxicity; pediatric patients; pharmacologic; postnatal; prevent; response; senescence; stem; 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的主要原因。中枢神经系统 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 在过去四十年中，各种治疗方法提高了生存率和治愈率。然而，超过一半的儿童 接受 xRT 治疗的患者会经历改变生活的神经认知障碍 (NI)，这尤其严重 在年轻时诊断的儿童中尤为突出。事实上，幼儿通常会表现出以下方面的障碍： xRT 后的学习、记忆、执行处理、视力和精细运动协调能力大大提高 比接受类似剂量治疗的成人更严重。尽管重要性显而易见 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 xRT 引起的神经毒性的驱动机制有限，目前尚不存在临床上有用的缓解剂。 细胞凋亡（程序性细胞死亡）是一种进化上保守的细胞死亡途径，对于正常细胞至关重要 发育、维持组织稳态和预防癌症。这条路径受到仔细控制 由 BCL-2 蛋白家族组成，该蛋白家族包含促凋亡和促存活成员，可控制 致力于细胞凋亡死亡。大多数抗癌疗法会诱导癌细胞或正常细胞凋亡 通过破坏 DNA 或微管等关键细胞成分或阻断关键信号传导途径。我们 发现在出生后的健康组织中细胞凋亡受到动态调节。本规定 驱动细胞命运决定以应对损伤或压力，并解释了为什么许多儿童 癌症治疗导致认知缺陷。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。然而尚不清楚 发育中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损失如何导致长期神经认知后遗症。 在此提案中，我们将 1) 在神经元、神经胶质细胞内的单细胞水平上比较 xRT 诱导的细胞命运 以及新生、幼年和成年小鼠大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 诱导的神经毒性的潜力 遗传或药理学（通过上游调节因子）的细胞凋亡以及细胞凋亡的长期影响 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，并奠定基础 为未来临床应用奠定基础，有意义地改善小儿脑癌的生活 幸存者及其家人。