Understanding brain extracellular matrix in the tumor microenvironment

了解肿瘤微环境中的脑细胞外基质

• 批准号: 10938468
• 负责人: Jennifer Hong
• 金额: $ 24.46万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-29 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10938468
• 关键词: Affect; Automobile Driving; Biological; Biology; Brain; Brain Neoplasms; Brain Pathology; Cells; Clinical; Complex; Computational Technique; Data Set; Development; Drug toxicity; Epilepsy; Evaluation; Extracellular Matrix; Glioma; Growth; Histological Techniques; Human; Interneurons; Invaded; Link; Machine Learning; Medical; Molecular; Molecular Structure; Morbidity - disease rate; Neurologic; Neurologic Symptoms; Neuronal Dysfunction; Neurons; Organism; Pathogenesis; Patients; Pharmaceutical Preparations; Proliferating; Quality of life; RNA; Recording of previous events; Recurrence; Refractory; Regulation; Research; Resources; Risk Factors; Role; Seizures; Specimen; Stromal Neoplasm; Structure; Synapses; System; Technology; Testing; Transcript; Tumor Promotion; digital; disability; epileptiform; experience; inhibitor; multidimensional data; neuronal tumor; novel; preservation; protein expression; single nucleus RNA-sequencing; successful intervention; therapeutic target; treatment strategy; tumor; tumor microenvironment; tumor progression

Seizures are a common, severe neurologic symptom of brain tumors with up to 80% of patients experiencing at least one seizure. Recurrent seizures, termed brain-tumor-related epilepsy (BTRE), develop in half of brain tumor patients and are often refractory to medical management. Poorly controlled epilepsy is the leading risk-factor for long-term disability in brain tumor patients and complicates the course of treatment due to drug toxicities, loss of driving privileges, and decreased quality of life. Further, an emerging body of work investigating neuronal regulation of glioma growth suggests that epileptiform activity promotes tumor proliferation and invasion. Successful intervention to stop seizures in patients would profoundly reduce neurologic morbidity and may halt tumor progression. However, current first-line therapy for BTRE, the drug Leviteracetam, a synaptic release inhibitor, fails to suppress seizures in half of patients. A fundamental shift in our approach to treatment of BTRE is greatly needed. Recent studies on the pathogenesis of tumor-related epilepsy have uncovered novel roles for the brain tumor microenvironment (TME), including tumor-stromal and tumor-neuron interactions that result in bidirectional, synergistic efforts to re-sculpt the molecular structure of the TME, resulting in neuronal dysfunction and a feed-forward loop of loss of inhibition, repeated seizures, and tumor progression. In particular, the perineuronal net (PNN) has been shown to be degraded by gliomas, resulting in dysregulation of inhibitory interneurons in the adjacent cortex. The TME is a novel and potentially powerful therapeutic target in BTRE; however, the molecular and cellular mechanisms connecting tumor microenvironment to clinical seizures in patients remain undefined. To better understand seizure onset in patients with brain tumors, this project will perform digital spatial profiling (DSP), an automated system for multiplexed, spatially-linked RNA transcript and protein expression quantification, and Visium 10x Single-nuclei RNA sequencing on brain tumor specimens to evaluate PNN structure and composition in the TME. The project will then apply machine-learning approaches to analyze these high-dimensional data in order to identify PNN features that relate to a clinical history of seizures. This aim will test the hypothesis that tumor-related PNN degradation in patients is associated with severe neurologic symptoms. It will also result in major development of novel histologic and computational techniques for evaluation of PNN structure and function that can be broadly applied to other, similarly complex biomedical datasets. Completion of these aims will help the Project Leader and research team to better understand how brain pathologies affect PNNs in patients, generate new biological resources and technologies for the study of human PNNs, and provide evidence to support preserving or restoring the PNN as a novel, more effective strategy for treatment of BTRE.

癫痫发作是脑肿瘤的一种常见的严重神经系统症状，高达80%的患者在 至少有一次癫痫发作复发性癫痫发作，称为脑肿瘤相关癫痫（BTRE），在一半的脑肿瘤中发展 患者，并且通常难以进行医疗管理。控制不佳的癫痫是主要的风险因素， 脑肿瘤患者的长期残疾，并且由于药物毒性、 驾驶特权和生活质量下降。此外，一个新兴的机构的工作，研究神经元 神经胶质瘤生长的调节表明癫痫样活动促进肿瘤增殖和侵袭。 成功的干预，以停止癫痫发作的患者将大大降低神经系统的发病率，并可能停止 肿瘤进展。然而，目前BTRE的一线治疗药物Leviteracetam，一种突触释放剂， 抑制剂未能抑制一半患者的癫痫发作。我们治疗BTRE方法的根本转变 非常需要。 最近对肿瘤相关癫痫发病机制的研究揭示了大脑的新作用 肿瘤微环境（TME），包括肿瘤-基质和肿瘤-神经元相互作用，导致双向， 协同努力重新塑造TME的分子结构，导致神经元功能障碍 以及失去抑制、反复癫痫发作和肿瘤进展的前馈回路。特别是 神经元周围网络（PNN）已被证明是由胶质瘤降解，导致抑制性神经元凋亡的失调。 相邻皮质的中间神经元TME是BTRE的一个新的和潜在的强大的治疗靶点; 然而，肿瘤微环境与临床癫痫发作之间的分子和细胞机制， 患者尚未明确。 为了更好地了解脑肿瘤患者的癫痫发作，该项目将进行数字空间 分析（DSP），用于多重、空间连接的RNA转录物和蛋白质表达的自动化系统 定量和Visium 10 x单核RNA测序，以评价PNN TME中的结构和组成。然后，该项目将应用机器学习方法来分析这些 高维数据，以便识别与癫痫发作的临床病史相关的PNN特征。这一目标将 检验患者中肿瘤相关PNN退化与严重神经系统疾病相关的假设。 症状这也将导致新的组织学和计算技术的重大发展，以评估 PNN的结构和功能，可以广泛应用于其他类似复杂的生物医学数据集。 这些目标的完成将有助于项目负责人和研究团队更好地了解大脑如何 病理影响患者的PNN，产生新的生物资源和技术，用于人类的研究。 PNN，并提供证据支持保留或恢复PNN作为一种新的，更有效的策略， BTRE的治疗