Integrative Molecular Epidemiology of Neurocognitive Outcomes in Acute Lymphoblastic Leukemia

项目摘要/摘要 这份K07职业发展奖提案详细说明了严格的培训、研究和指导计划 这将为布朗博士开启成功的独立研究生涯奠定基础。布朗医生的 长期的职业目标是建立一个富有成效的独立研究计划，重点是 寻找新的生物标志物和可修改的治疗靶点以减轻与治疗相关的负担 儿童癌症患者的毒性。因此，这一提议的研究目标是早期表征 化疗相关性神经认知障碍的表型、代谢和基因组生物标志物 儿童急性淋巴细胞白血病(ALL)患者。尽管改进的治疗方案对儿童ALL 导致存活率超过90%，近一半的患者经历了与慢性治疗相关的 神经认知功能障碍。这一建议遵循这样的假设，即中枢神经系统引导所有 化疗破坏脑脊液代谢平衡，表现为急性 症状毒性和长期神经认知功能障碍。因为遗传因素很可能控制着脑脊液 代谢组对治疗的反应，我们进一步假设，整合遗传和代谢组学数据将 导致了因果遗传路径的发现。这项提案的具体研究目标将评估 是否：1)所有治疗的诱导后阶段的症状毒性反映了化疗的指导 神经损伤，并作为治疗后神经认知能力的早期标志；2)ALL 化疗导致正常脑脊液代谢途径的一致和可识别的变化 神经认知功能和发育；以及3)遗传变异改变个体对 神经认知障碍。利用美国国立卫生研究院资助的两项具有丰富表型数据和生物素的研究 存储库，这项创新的提议将建立最大的前瞻性调查之一 儿童急性淋巴细胞白血病患者的神经认知结果。在此过程中获得的研究经验 学习是对拟议的职业发展目标的补充。具体地说，教学培训和互动 在分子流行病学(Scheurer博士)、症状研究(Hockenberry博士)、 代谢组学(Devaraj博士)和神经心理学(Ris博士)将加强Brown博士的内容领域：1) 熟悉患者报告的症状和神经认知评估；2)了解代谢组学 研究方法；3)精通拨款和科学写作。全面的职业发展 该提案中概述的研究计划将解决布朗博士培训中的主要差距，提供更多 研究经验，并作为初步数据的独特来源，支持未来的研究工作。

Project Summary/Abstract This K07 Career Development Award proposal details the rigorous training, research, and mentorship program that will provide a foundation for Dr. Brown to launch a successful independent research career. Dr. Brown’s long-term career goal is to establish a productive independent research program, with an emphasis on identifying novel biomarkers and modifiable therapeutic targets to reduce the burden of treatment-related toxicity among pediatric cancer patients. Therefore, the research goal for this proposal is to characterize early phenotypic, metabolomic, and genomic biomarkers of chemotherapy-associated neurocognitive impairment in pediatric acute lymphoblastic leukemia (ALL) patients. Although improved treatment regimens for pediatric ALL have resulted in survival rates exceeding 90%, nearly half of patients experience chronic treatment-related neurocognitive dysfunction. This proposal pursues the hypothesis that central nervous system-directed ALL chemotherapy disrupts the equilibrium of cerebral spinal fluid (CSF) metabolome, manifesting as acute symptom toxicity and long-term neurocognitive dysfunction. Because genetic factors likely control the CSF metabolomic response to therapy, we further hypothesize that integrating genetic and metabolomics data will lead to the discovery of causal genetic pathways. The specific research aims of this proposal will evaluate whether: 1) Symptom toxicity during the post-induction phase of ALL therapy reflects chemotherapy-directed neurologic damage and serves as an early marker of post-treatment neurocognitive performance; 2) ALL chemotherapy induces consistent and recognizable changes to CSF metabolomic pathways involved in normal neurocognitive function and development; and 3) Genetic variation modifies individual susceptibility to neurocognitive impairment. Leveraging two NIH-funded studies with rich phenotype data and biospecimen repositories, this innovative proposal will establish one of the largest prospective investigations of neurocognitive outcomes in pediatric ALL patients. The research experience gained during the course of this study complements the proposed career development goals. Specifically, didactic training and interaction with experienced mentors in molecular epidemiology (Dr. Scheurer), symptoms research (Dr. Hockenberry), metabolomics (Dr. Devaraj), and neuropsychology (Dr. Ris) will enhance Dr. Brown’s: 1) Content area expertise in patient-reported symptoms and neurocognitive evaluation; 2) Understanding of metabolomics research methods; and 3) Proficiency in grant and scientific writing. The comprehensive career development and research plan outlined in this proposal will address key gaps in Dr. Brown’s training, provide additional research experience, and serve as a unique resource of preliminary data to support future research endeavors.