Integrative Molecular Epidemiology of Neurocognitive Outcomes in Acute Lymphoblastic Leukemia

项目总结/摘要 此K 07职业发展奖提案详细说明了严格的培训，研究和指导计划 这将为布朗博士开展成功的独立研究事业奠定基础。布朗博士的 长期职业目标是建立一个富有成效的独立研究计划，重点是 确定新的生物标志物和可改变的治疗靶点，以减少治疗相关的负担 儿童癌症患者中的毒性。因此，本提案的研究目标是尽早表征 化疗相关性神经认知障碍的表型、代谢组学和基因组学生物标志物 儿童急性淋巴细胞白血病（ALL）患者。尽管儿童ALL的治疗方案有所改善， 导致生存率超过90%，近一半的患者经历慢性治疗相关的 神经认知功能障碍这项提议追求的假设是，中枢神经系统指导的ALL 化疗破坏了脑脊液（CSF）代谢组的平衡，表现为急性 症状毒性和长期神经认知功能障碍。因为遗传因素可能控制脑脊液 代谢组学对治疗的反应，我们进一步假设，整合遗传和代谢组学数据将 导致了因果遗传途径的发现。本提案的具体研究目标将评估 是否：1）ALL治疗诱导后阶段的症状毒性反映了化疗导向 神经损伤，并作为治疗后神经认知表现的早期标志物; 2）ALL 化疗诱导CSF代谢组学途径的一致和可识别的变化，这些代谢途径涉及正常 神经认知功能和发育; 3）遗传变异改变个体对神经系统疾病的易感性。 神经认知障碍利用两项NIH资助的研究，提供丰富的表型数据和生物样本 储存库，这一创新的建议将建立一个最大的前瞻性调查， 儿童ALL患者的神经认知结局。在此过程中获得的研究经验 研究补充了拟议的职业发展目标。具体而言，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）将增强Brown博士的：1）内容领域 患者报告症状和神经认知评估方面的专业知识; 2）了解代谢组学 研究方法; 3）精通基金和科学写作。全面的职业发展 本提案中概述的研究计划将解决布朗博士培训中的关键差距，提供额外的 研究经验，并作为一个独特的初步数据资源，以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.