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Circadian regulation of cancer therapy-associated neuroinflammation

癌症治疗相关神经炎症的昼夜节律调节

基本信息

批准号：
10666634
负责人：
Erin G Valdez
金额：
$ 18.84万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666634
关键词：
Adult Affect Aftercare Age Astrocytes Attention Blood - brain barrier anatomy Brain Cancer Biology Cancer Detection Cancer Etiology Cancer Survivor Cell Lineage Cells Central Nervous System Childhood Chronic Clinical Cognition Cognitive Cognitive deficits Data Development Dose Endothelial Cells Etiology Exhibits Exposure to Gene Expression Gene Expression Profile Glean Goals Healthcare Systems Hour Immune Immunologic Factors Impaired cognition Impairment In Vitro Incidence Individual Inflammatory Intrinsic drive Knowledge Language Learning Life Malignant Neoplasms Mediating Memory Methotrexate Microglia Motor Mus Myelin Neurocognitive Neuroglia Neurologic Neurologic Deficit Neurologic Dysfunctions Oligodendroglia Outcome Patients Permeability Phase Pre-Clinical Model Predisposition Quality of life Research Role Severities Short-Term Memory Structure Survivors Syndrome System Testing Therapeutic Thinness Time Toxic effect Treatment Protocols Treatment-Related Cancer United States Withholding Treatment Work blood-brain barrier function blood-brain barrier permeabilization brain cell cancer therapy cancer type cell type chemotherapeutic agent chemotherapy circadian circadian pacemaker circadian regulation cognitive function density executive function experience glial activation improved in vivo information processing mouse model multitask myelination nervous system disorder neuroinflammation novel oligodendrocyte lineage pre-clinical response side effect therapeutically effective transcriptome transcriptome sequencing transcriptomics

项目摘要

Recent advances in cancer therapy have increased survivability of numerous pediatric and adult cancers. By 2023, over 20 million cancer survivors will live in the United States. Unfortunately, the vast majority of these individuals will exhibit some indication of sustained neurological deficiency, clinically called cancer therapy- related cognitive impairment (CRCI). These impairments include deficits in memory, learning, attention, executive function, information processing, language, and multitasking. Despite the myriad suspected causes of CRCI, one of the main commonalities is a persistent neuroinflammatory state following cancer treatment. How this sustained neuroinflammation is mediated remains a critical gap in our understanding of the underlying biology of CRCI. Our previous work in a preclinical mouse model demonstrated that the commonly used chemotherapeutic agent, methotrexate (MTX), induces tri-glial dysregulation that is dependent on the direct activation of microglia, the resident immune cells of the central nervous system. Systemic MTX administration results in persistent microglial pan activation which promotes astrocyte reactivity and decreased OPC density and differentiation into myelin-forming oligodendrocytes, leading to thinner myelin. MTX-induced aberrant myelination causes persistent cognitive deficits associated with CRCI, including decrements in short-term memory and attention for up to six months post-treatment. Preliminary data from our lab demonstrates that this microglial activation, and consequent dysregulation of oligodendrocyte lineage cells, is time-of-day dependent, suggesting that the sustained microglial activation and clinical deficiency associated with CRCI may be regulated in a circadian manner and thus susceptible to chronomodulation. The objective of this proposal is to determine if MTX chemotherapy drives intrinsic changes to the microglial transcriptome and alters the structure or function of the BBB to sustain the activation of microglia associated with CRCI. Our central hypothesis is that chemotherapy-induced chronic neuroinflammation is modulated by circadian regulation of microglia and the BBB. Our approach to testing this hypothesis is to expose microglia in vitro and in vivo to MTX chemotherapy at different circadian phases and analyze the transcriptional profile of isolated microglia and BBB endothelial cells, as well as assess BBB permeability and integrity. The rationale for this approach is that information gleaned from the results will contribute mechanistic understanding into the intrinsic and microenvironmental modulators of neuroinflammatory microglia following cancer therapy. Upon completion of this proposal, we expect to have identified how circadian modulation dictates microglial activation to chemotherapy. There remains an urgent need to define the underlying mechanisms of neuroinflammation mediating the persistent neurological dysregulation in CRCI in preclinical models of cancer therapy. In the absence of such knowledge, effective therapeutic strategies aimed at mitigating neuroinflammation will remain elusive and subsequent sustained neurological deficits will continue to be a substantive burden to cancer survivors and our healthcare system.

癌症治疗的最新进展提高了许多儿童和成人癌症的生存率。经过到 2023 年，美国将有超过 2000 万癌症幸存者。不幸的是，其中绝大多数个体会表现出一些持续神经缺陷的迹象，临床上称为癌症治疗- 相关认知障碍（CRCI）。这些障碍包括记忆力、学习力、注意力、执行功能、信息处理、语言和多任务处理。尽管有无数可疑的原因 CRCI 的主要共同点之一是癌症治疗后持续存在的神经炎症状态。如何这种持续的神经炎症的介导仍然是我们理解其潜在机制的一个关键差距 CRCI 生物学。我们之前在临床前小鼠模型中的工作表明，常用的化疗药物甲氨蝶呤 (MTX) 会诱导三胶质细胞失调，而这种失调依赖于直接激活小胶质细胞，即中枢神经系统的常驻免疫细胞。全身 MTX 给药导致小胶质细胞持续激活，从而促进星形胶质细胞反应性并降低 OPC 密度并分化为形成髓磷脂的少突胶质细胞，导致髓磷脂变薄。 MTX诱导的异常髓鞘形成导致与 CRCI 相关的持续认知缺陷，包括短期认知能力下降治疗后长达六个月的记忆力和注意力。我们实验室的初步数据表明，小胶质细胞的激活以及随之而来的少突胶质细胞谱系细胞的失调，是一天中时间依赖性的，表明与 CRCI 相关的持续小胶质细胞激活和临床缺陷可能受到调节以昼夜节律方式进行，因此容易受到时间调节的影响。该提案的目的是确定 MTX 化疗是否会导致小胶质细胞转录组发生内在变化并改变其结构或功能 BBB 维持与 CRCI 相关的小胶质细胞的激活。我们的中心假设是化疗引起的慢性神经炎症是通过小胶质细胞的昼夜节律调节来调节的 BBB。我们检验这一假设的方法是在体外和体内将小胶质细胞暴露于 MTX 化疗中不同的昼夜节律阶段并分析分离的小胶质细胞和 BBB 内皮细胞的转录谱，以及评估 BBB 渗透性和完整性。这种方法的基本原理是从收集的信息研究结果将有助于对内在和微环境调节剂的机制理解癌症治疗后的神经炎症小胶质细胞。完成本提案后，我们预计确定了昼夜节律调节如何决定小胶质细胞激活以进行化疗。仍有紧急情况需要定义介导持续性神经系统炎症的神经炎症的潜在机制癌症治疗临床前模型中 CRCI 的失调。在缺乏这些知识的情况下，有效的旨在减轻神经炎症的治疗策略仍然难以捉摸，并且随后会持续下去神经缺陷将继续成为癌症幸存者和我们的医疗保健系统的重大负担。