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科和成人癌症的生存能力。经过 2023年，超过2000万癌症幸存者将居住在美国。不幸的是，其中绝大多数个体将表现出持续神经缺乏症的某种迹象，临床称为癌症治疗 - 相关认知障碍（CRCI）。这些障碍包括记忆，学习，注意力，执行功能，信息处理，语言和多任务处理。尽管有无数的怀疑原因 CRCI是癌症治疗后的持续性神经炎症状态之一。如何介导这种持续的神经炎症是我们对基础的理解的关键差距 CRCI的生物学。我们以前在临床前鼠标模型中的工作证明了常用的化学治疗剂，甲氨蝶呤（MTX），诱导了取决于直接的三膜失调小胶质细胞激活，中枢神经系统的驻留免疫细胞。系统性MTX给药导致持续的小胶质锅激活，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，导致髓磷脂较薄。 MTX引起的异常髓鞘形成导致与CRCI相关的持续认知缺陷，包括短期减少治疗后长达六个月的记忆和关注。我们实验室的初步数据表明这是小胶质细胞的激活以及少突胶质细胞谱系细胞的失调，是依赖时间的，表明可以调节与CRCI相关的持续小胶质激活和临床缺乏以昼夜节律的方式，因此容易受到时间调节的影响。该提议的目的是确定如果MTX化学疗法驱动小胶质细胞转录组的内在变化并改变结构或功能 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学疗法诱导的慢性神经炎症是由小胶质细胞调节和 BBB。我们检验该假设的方法是在体外和体内暴露于MTX化学疗法的小胶质细胞不同的昼夜节相，并分析分离的小胶质细胞和BBB内皮细胞的转录曲线，以及评估BBB的渗透性和完整性。这种方法的理由是从中收集的信息结果将有助于对机械理解，以了解癌症治疗后的神经炎性小胶质细胞。该提议完成后，我们希望确定了昼夜节律如何决定化学疗法的小胶质细胞激活。仍然很紧急需要定义介导持续神经系统神经炎症的基本机制癌症治疗临床前模型中CRCI的失调。在没有这种知识的情况下，有效旨在减轻神经炎症的治疗策略将保持难以捉摸，随后持续神经缺陷将继续给癌症幸存者和我们的医疗保健系统带来实质性负担。