Aging-Related Biomarkers of Neurocognitive Function in Long-term Hodgkin Lymphoma Survivors

长期霍奇金淋巴瘤幸存者神经认知功能的衰老相关生物标志物

• 批准号: 10323037
• 负责人: AnnaLynn Williams
• 金额: $ 12.34万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-03 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323037
• 关键词: Acceleration; Adolescent and Young Adult; Aftercare; Age; Aging; Attention; Automobile Driving; Behavior Therapy; Biological; Biological Aging; Biological Markers; Blood - brain barrier anatomy; Brain; CD4/CD8 ratio procedure; Cancer Biology; Cancer Control; Cancer Survivor; Cancer Survivorship; Cell Aging; Childhood Hodgkin' s Lymphoma; Chronic; Chronology; Clinical; Cognitive aging; Communities; Complex; Data; Development; Development Plans; Ensure; Environment; Epidemiologist; Epigenetic Process; Exercise; Exposure to; Frequencies; Future; General Population; Grant; Health; Hodgkin Lymphoma survivors; Immune; Impaired cognition; Impairment; Inflammaging; Inflammation; Inflammation Mediators; Interleukin-6; International; Intervention; Intervention Trial; Lead; Length; Long-Term Survivors; Malignant Childhood Neoplasm; Malignant Neoplasms; Malondialdehyde; Mediating; Memory; Mentors; Modeling; Modification; Molecular; Molecular Epidemiology; Morbidity - disease rate; Mortality Decline; Neuraxis; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Neuropsychology; Oxidative Stress; Patient Self-Report; Pediatric Neoplasm; Phase; Physiological; Population; Positioning Attribute; Premature aging syndrome; Process; Quality of life; Recovery; Research; Research Personnel; Resources; Risk; Risk Factors; Saint Jude Children' s Research Hospital; Siblings; Smoking; Statistical Methods; Survivors; TNF gene; Time; Training; adverse outcome; base; cancer therapy; career development; childhood cancer survivor; cognitive reserve; cohort; comorbidity; critical period; cytokine; design; effective intervention; experience; frailty; glutathione peroxidase; high risk population; immunosenescence; inflammatory marker; mild cognitive impairment; modifiable risk; mortality; neurocognitive test; neuroinflammation; neuropathology; nutrition; oxidized low density lipoprotein; premature; prevent; recruit; reduce symptoms; senescence; skills; social; systemic inflammatory response; telomere; therapy development

Abstract Emerging evidence suggests that childhood cancer survivors treated without central nervous system (CNS) directed therapies are at significant risk for neurocognitive impairment that is associated with decreased social attainment and quality of life. However, the underlying biological mechanisms of neurocognitive impairment in this population are poorly understood limiting our ability to prevent or alleviate these adverse outcomes. Long- term survivors of childhood cancer have a higher frequency of frailty and chronic health conditions than sibling controls suggesting cancer therapy may accelerate the physiological and biological aging process, which may lead to neurocognitive impairment. Studies in the general population indicate systemic inflammation and oxidative stress increase with age and are associated with increased morbidity, mortality, and cognitive decline. Inflammation and oxidative stress are also important regulators of telomere length and epigenetic changes which have been associated with neurocognitive impairment in aging non-cancer populations. These biomarkers have yet to be extensively examined in childhood cancer survivors treated without CNS directed therapies. The objective of this K99R00 is to identify aging-related biological predictors of neurocognitive impairment and subsequent decline in order to inform the design of future interventions using existing data and biospecimens from 300 HL survivors and 200 community controls in the St. Jude Lifetime cohort. Specifically, the K99 phase aims to examine cross-sectional associations between markers of inflammation, oxidative stress, immunosenescence, and cellular aging (telomere length and epigenetic age acceleration) with neurocognitive impairment in long-term Hodgkin lymphoma survivors (HL). The R00 phase will expand on these findings by first describing the trajectory of neurocognitive decline in long-term HL survivors and then by examining longitudinal associations between these biomarkers and subsequent neurocognitive decline. Further, these studies will provide data on the influence of modifiable risk factors (e.g. exercise, smoking, nutrition) on these biomarkers to inform future development of interventions to mitigate neurocognitive impairment in cancer survivors. Dr. Williams is an emerging translational cancer control epidemiologist focused on underlying pathophysiologic and biologic mechanisms of neurocognitive function in cancer survivors. The K99R00 allows Dr. Williams to develop expertise in 1) neurobiology and cancer biology and treatment specific to HL, 2) aging-related biomarkers and molecular epidemiology, 3) complex statistical methods and 4) clinical and behavioral intervention trials. Dr. Williams' mentoring team has extensive expertise in neurocognitive assessments, neuropathology, molecular epidemiology, childhood cancer, and statistical methods. St. Jude Children's Research Hospital is an international leader in cancer control and survivorship and provides a resource-rich training environment for Dr. Williams. The combined training and research plan will ensure Dr. Williams' transition to independence by providing the skills and preliminary data to successfully compete for future R01-level grants.

抽象的 新兴证据表明，未经中枢神经系统（CNS）治疗的儿童癌症幸存者 定向疗法有明显的神经认知障碍风险，与社会降低有关 成就和生活质量。但是，神经认知障碍的潜在生物学机制 该人群鲜为人知，限制了我们预防或减轻这些不利结果的能力。长的- 儿童癌症的期限幸存者比同学的频率更高 表明癌症治疗的对照可能会加速生理和生物衰老过程，这可能 导致神经认知障碍。一般人群的研究表明全身性炎症和 氧化应激随着年龄的增长而增加，并且与发病率，死亡率和认知能力下降有关。 炎症和氧化应激也是端粒长度和表观遗传变化的重要调节剂 与衰老的非癌症人群中的神经认知障碍有关。这些生物标志物具有 然而，在未经CNS的指示疗法的儿童癌症幸存者中进行了广泛的检查。这 该K99R00的目的是确定与衰老相关的神经认知障碍和 随后的下降，以便使用现有数据和生物测量来告知未来干预措施的设计 来自圣裘德一生队列中的300 hl幸存者和200个社区控制。具体而言，K99阶段 旨在检查炎症标记，氧化应激标记之间的横截面关联， 具有神经认知的免疫衰老和细胞衰老（端粒长度和表观遗传年龄加速度） 长期霍奇金淋巴瘤幸存者（HL）的损害。 R00阶段将首先扩展这些发现 描述长期HL幸存者的神经认知能力下降的轨迹，然后检查纵向 这些生物标志物与随后的神经认知能力下降之间的关联。此外，这些研究将 提供有关可修改风险因素（例如运动，吸烟，营养）影响的数据 告知未来开发干预措施，以减轻癌症幸存者的神经认知障碍。博士 威廉姆斯是一位新兴的转化癌症控制流行病学家，专注于潜在的病理生理学和 癌症幸存者神经认知功能的生物学机制。 K99R00允许威廉姆斯博士发展 1）神经生物学和癌症生物学以及特定于HL的治疗，2）与衰老有关的生物标志物和 分子流行病学，3）复杂的统计方法和4）临床和行为干预试验。博士 威廉姆斯的指导团队在神经认知评估，神经病理学，分子方面具有广泛的专业知识 流行病学，儿童癌和统计方法。圣裘德儿童研究医院是 国际癌症控制和生存领域的领导者，为博士提供了资源丰富的培训环境 威廉姆斯。联合培训和研究计划将确保威廉姆斯博士通过 提供技能和初步数据，以成功竞争未来的R01级赠款。