Identification of causal factors underlying cognitive deficits in a mouse model of childhood leukemia survival

识别儿童白血病存活小鼠模型中认知缺陷的致病因素

基本信息

批准号：
10256061
负责人：
TERESA M REYES
金额：
$ 58.48万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-07 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10256061
关键词：
5 year old Acute Lymphocytic Leukemia Adolescence Adolescent Adult Affect Aftercare Antioxidants Area Attention Automobile Driving Brain CCL2 gene Cancer Model Cell Line Cells Cerebrospinal Fluid Chemotherapy-Oncologic Procedure Child Childhood Childhood Leukemia Cognitive Cognitive deficits Development Dietary Intervention Executive Dysfunction Exposure to Folic Acid Gene Expression Profile Genes Genetic Transcription Homocysteine ITGAM gene Immune Impaired cognition Inflammation Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Interruption Intervention Leucovorin Leukemic Cell Life Link Macrophage-1 Antigen Malignant Childhood Neoplasm Malignant Neoplasms Mediating Memory impairment Methotrexate Microglia Mus N-Acetylcysteinamide Outcome Oxidative Stress Pathway interactions Patients Phagocytes Pharmaceutical Preparations Plasma Prefrontal Cortex Quality of life Reporting Risk Role Short-Term Memory Solid Source Supplementation Survival Rate Survivors Synapses Testing Time Vincristine Vitamin B Complex cell growth chemotherapeutic agent chemotherapy childhood cancer survivor cognitive function dietary executive function experimental study flexibility folic acid metabolism gray matter improved leukemia mouse model myelination negative affect neuroinflammation novel therapeutics postnatal reduce symptoms response side effect single-cell RNA sequencing standard of care synaptic function synaptic pruning synaptogenesis therapy development white matter white matter damage young adult

项目摘要

Abstract Survival rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer, are now close to 90%, but survivors of childhood cancer are at an increased risk for long term cognitive deficits, particularly affecting executive function (e.g., attention, planning, inhibitory control, cognitive flexibility). The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients, and is closely associated with executive function deficits. Thus a pressing need exists to define the mechanisms that link MTX exposure to cognitive dysfunction, to guide development of intervention strategies to protect the developing brain, reduce symptoms and optimize quality of life in ALL survivors, during childhood, adolescence, young and full adulthood. To that end, we have developed a translationally relevant mouse model of leukemia survival that combines cancer exposure (mouse leukemic cell line (L1210 cells) with contemporary chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) administered during early life. PFC development extends through adolescence, which renders this area of the brain particularly vulnerable to early life chemotherapy. Providing a solid premise for the proposed experiments, our mouse model recapitulates executive function deficits observed in ALL patients. Additionally, in response to early life cancer + chemotherapy, we have found an increase in the proinflammatory molecules IL-1 and CCL2, as well as a decrease in white matter associated genes within the PFC. In Aim 1, single cell RNA sequencing will be used to define the effects of cancer and/or chemotherapy on the transcriptional profile of the PFC. MTX disrupts folate metabolism to inhibit cell growth, but this disruption also leads to increased levels of the proinflammatory metabolite, homocysteine (HCY), in both plasma and cerebrospinal fluid. Increased HCY can drive inflammation, oxidative stress and is associated with both white and gray matter damage, as well as cognitive impairment. Further executive function deficits have also been linked to altered synaptic function, and microglia, a brain resident immune cell, can contribute to synapse elimination via the CD11b(CR3)-C3 phagocytic pathway. Therefore, we hypothesize that MTX-driven increased HCY levels will lead to neuroinflammation and oxidative stress, leading to gray and white matter damage, and altered synaptic pruning in the prefrontal cortex, which underlie deficits in executive function. To test this hypothesis, HCY-lowering strategies (folate and B vitamin supplementation, or the antioxidant, N-acetylcysteine amide) will be evaluated in Aim 2. Aim 3 will test the necessity of IL-1 activity while Aim 4 will test the necessity of microglia in mediating the chemotherapy-associated cognitive deficits, as well as neuroinflammation and oxidative stress, leading to gray and white matter damage, and altered synaptic pruning in the prefrontal cortex

抽象的最常见的儿童癌症急性淋巴细胞白血病 (ALL) 的生存率目前为接近 90%，但儿童癌症幸存者出现长期认知缺陷的风险增加，尤其影响执行功能（例如注意力、计划、抑制控制、认知灵活性）。化疗药物甲氨蝶呤 (MTX) 用于治疗大多数 ALL 患者，并且密切相关与执行功能缺陷有关。因此，迫切需要定义链接的机制 MTX 暴露于认知功能障碍，指导制定干预策略以保护开发大脑，减轻症状并优化所有幸存者童年时期的生活质量，青春期、青年期和成年期。为此，我们开发了一种与转化相关的白血病存活小鼠模型将癌症暴露（小鼠白血病细胞系（L1210细胞）与当代化疗结合起来生命早期服用的药物（长春新碱和 MTX，以及亚叶酸救援）。 PFC开发延伸到青春期，这使得大脑的这个区域特别容易受到早期生活的影响化疗。我们的小鼠模型概括了为所提出的实验提供了坚实的前提在所有患者中观察到执行功能缺陷。此外，针对早期癌症+ 化疗期间，我们发现促炎分子 IL-1 和 CCL2 以及 PFC 内白质相关基因减少。在目标 1 中，单细胞 RNA 测序将是用于定义癌症和/或化疗对 PFC 转录谱的影响。 MTX 会破坏叶酸代谢以抑制细胞生长，但这种破坏也会导致叶酸水平升高血浆和脑脊液中促炎代谢物同型半胱氨酸 (HCY) 的含量。增加 HCY 可以引发炎症、氧化应激，并与白质和灰质损伤有关，以及认知障碍。进一步的执行功能缺陷也与改变有关突触功能和小胶质细胞（一种大脑常驻免疫细胞）可以通过以下方式促进突触消除： CD11b(CR3)-C3 吞噬途径。因此，我们假设 MTX 驱动的 HCY 增加水平会导致神经炎症和氧化应激，导致灰质和白质损伤，并且前额皮质突触修剪的改变是执行功能缺陷的基础。为了检验这一假设，降低 HCY 的策略（叶酸和 B 族维生素补充剂，或抗氧化剂（N-乙酰半胱氨酸酰胺）将在目标 2 中进行评估。目标 3 将测试 IL-1 活性的必要性而目标 4 将测试小胶质细胞介导化疗相关认知的必要性缺陷以及神经炎症和氧化应激，导致灰质和白质损伤，以及前额皮质突触修剪的改变