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.

癫痫发作是脑肿瘤常见的严重神经系统症状，高达 80% 的患者会出现癫痫发作 至少一次癫痫发作。一半的脑肿瘤患者会出现反复发作，称为脑肿瘤相关性癫痫 (BTRE) 患者通常难以接受医疗管理。癫痫控制不良是导致癫痫发作的主要危险因素 脑肿瘤患者长期残疾，并且由于药物毒性、丧失功能而使治疗过程复杂化 驾驶特权，以及生活质量下降。此外，一项新兴的研究神经元的工作 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。 成功干预患者癫痫发作将大大降低神经系统发病率，并可能停止癫痫发作 肿瘤进展。然而，目前 BTRE 的一线疗法是左旋西坦药物，一种突触释放药物 抑制剂，无法抑制一半患者的癫痫发作。我们治疗 BTRE 方法的根本转变 是非常需要的。 最近对肿瘤相关癫痫发病机制的研究发现了大脑的新作用 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、 synergistic efforts to re-sculpt the molecular structure of the TME, resulting in neuronal dysfunction 以及抑制丧失、反复癫痫发作和肿瘤进展的前馈循环。特别是， 神经周围网络（PNN）已被证明会被神经胶质瘤降解，导致抑制性失调 相邻皮层的中间神经元。 TME 是 BTRE 中一个新颖且潜在强大的治疗靶点； 然而，将肿瘤微环境与临床癫痫发作联系起来的分子和细胞机制 患者仍不明确。 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)，一种用于多重、空间关联的 RNA 转录物和蛋白质表达的自动化系统 对脑肿瘤标本进行定量和 Visium 10x 单核 RNA 测序以评估 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，以便识别与癫痫临床病史相关的 PNN 特征。这一目标将 检验患者肿瘤相关 PNN 退化与严重神经系统疾病相关的假设 症状。它还将导致用于评估的新型组织学和计算技术的重大发展 的 PNN 结构和功能，可广泛应用于其他类似的复杂生物医学数据集。 完成这些目标将有助于项目负责人和研究团队更好地了解大脑如何 病理学影响患者的 PNN，为人类研究产生新的生物资源和技术 PNN，并提供证据支持保留或恢复 PNN 作为一种新颖、更有效的策略 BTRE 的治疗。