Aberrant Signaling from Brain Tumors Regulates Distant and Local Environments

脑肿瘤的异常信号调节远距离和局部环境

• 批准号: 10610104
• 负责人: Kaysaw C Tuy
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610104
• 关键词: Award; Bioenergetics; Biological Assay; Biology; Blood - brain barrier anatomy; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone remodeling; Brain; Brain Neoplasms; Brain Pathology; Cell Death; Cell Maintenance; Cell Survival; Cells; Cellular Metabolic Process; Clinical; Communication; Cues; Data; Denervation; Development; Disease; Disease Progression; Distant; Dopa-Responsive Dystonia; Environment; Enzymes; Epigenetic Process; Fibroblasts; GTP Cyclohydrolase; GTP Cyclohydrolase I; Genes; Genetic Transcription; Genomic Instability; Glioblastoma; Glioma; Glucose; Growth; Hematologic Agents; Hematologic Neoplasms; Hematopoietic stem cells; Immune; Immunosuppression; Immunotherapy; Infiltration; Inflammation; Intervention; Investigation; Iron; Link; Lipid Peroxidation; Lipids; Lymphopenia; Maintenance; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolism; Modeling; Myelogenous; Myeloid-derived suppressor cells; Myelopoiesis; Neurodegenerative Disorders; Nitric Oxide; Non-Malignant; Nonesterified Fatty Acids; Nutrient; Oxidation-Reduction; Oxidative Stress; Palmitates; Parkinson Disease; Pathology; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Production; Publishing; Reactive Oxygen Species; Recurrence; Regulation; Reporting; Research; Resistance; Role; Sensory Receptors; Signal Transduction; Supporting Cell; Therapeutic; Therapeutic Intervention; Training; Vascularization; Work; biological adaptation to stress; cancer cell; cell growth; cofactor; experience; improved; inhibitor; lipid metabolism; metabolomics; nerve stem cell; nerve supply; nervous system disorder; neurotransmission; neurotransmitter uptake; novel; nutrient deprivation; oxidative damage; patient prognosis; preclinical study; preservation; progenitor; recruit; relating to nervous system; stem-like cell; tetrahydrobiopterin; transcriptomics; tumor; tumor microenvironment

ABSTRACT Perturbations in redox signaling are associated with multiple neurological disorders, ranging from neurodegenerative diseases to brain tumors. The brain tumor glioblastoma (GBM) is a devastating disease and improved understanding of its altered bioenergetics and redox status is likely to improve treatment options. GBM is highly heterogeneous and includes cells that have altered redox states and similarities to neural stem cells, called brain tumor initiating cells (BTICs), that cause tumor recurrence. A redox regulator we identified as being elevated in BTICs is GTP cyclohydrolase I (GCH1), a gene known to be altered in dopa-responsive dystonia and Parkinson’s disease. Importantly, GCH1, a rate-limiting enzyme that produces tetrahydrobiopterin (BH4), maintains BTIC survival via suppressing damage caused by reactive oxygen species (ROS). Mitigating ROS via GCH1 is one mechanism by which BTICs may survive hostile tumor microenvironments, like nutrient deprivation. As redox biology and metabolism are closely linked, I hypothesize that the metabolic consequence of high GCH1 confers protection to oxidatively vulnerable lipids to support BTIC growth. My current findings during the F99 phase strongly suggest that the GCH1/BH4 pathway increases lipid utilization and plays a vital role in protecting oxidatively vulnerable lipids during metabolic reprogramming. The successful investigation of oxidative stress responses via GCH1 and its relationship with metabolism will reveal metabolic vulnerabilities for clinical intervention. In addition, my studies are likely to be informative for other neurodegenerative diseases where GCH1 is altered, or ROS is unregulated. For the K99 phase, continued studies in brain tumor models will shift focus toward elucidating the impact of GBM on the bone marrow (BM) microenvironment in regulating immune suppression and myeloid recruitment. Infiltrating BM cells are a significant contributor to the tumor microenvironment where GBM co-opts these cells to drive disease progression. Brain tumors are excitatory cells that readily release/uptake neurotransmitters for their growth, but this high neural activity has not been investigated in the BM, despite the BM being innervated. BM cells have several neuroreceptors, suggesting these cells can readily respond to neural cues. As BM innervation is important for its maintenance and immune mobilization, aberrant neural activity from GBM that remodel the BM is unexplored. Therefore, using BM denervation studies in GBM models, I will assess neural activity as a critical player in myeloid skewing in the BM and recruit immunosuppressive myeloid cells to the brain. Elucidating the crosstalk between glioma-to-bone marrow through neural communication provides an opportunity to disrupt signaling pharmacologically without having to consider drugs for blood brain barrier penetrance.

摘要 氧化还原信号的紊乱与多种神经系统疾病有关， 神经退行性疾病和脑瘤脑肿瘤胶质母细胞瘤（GBM）是一种毁灭性的疾病， 对其改变的生物能量学和氧化还原状态的更好理解可能会改善治疗选择。GBM 是高度异质性的并且包括具有改变的氧化还原状态和与神经干细胞相似性的细胞， 称为脑肿瘤起始细胞（BTIC），导致肿瘤复发。一种氧化还原调节剂， 在BTIC中升高的是GTP环化水解酶I（GCH 1），其是已知在多巴反应性肌张力障碍中改变的基因， 帕金森氏症。重要的是，GCH 1是一种产生四氢生物蝶呤（BH 4）的限速酶， 通过抑制活性氧（ROS）引起的损伤维持BTIC存活。通过以下途径减轻ROS GCH 1是BTIC可以在不利的肿瘤微环境中生存的一种机制，如营养剥夺。 由于氧化还原生物学和代谢密切相关，我假设高GCH 1的代谢结果 保护易氧化的脂质以支持BTIC生长。我目前在F99期间的发现 阶段强烈表明GCH 1/BH 4途径增加脂质利用，并在保护 在代谢重编程过程中氧化脆弱的脂质。氧化应激的成功研究 通过GCH 1的反应及其与代谢的关系将揭示临床应用的代谢脆弱性。 干预此外，我的研究可能对其他神经退行性疾病提供信息， GCH 1改变，或ROS不受调节。 对于K99阶段，在脑肿瘤模型中的继续研究将把重点转向阐明GBM的影响 在调节免疫抑制和髓系募集中对骨髓（BM）微环境的影响。 浸润的BM细胞是GBM吸收这些细胞的肿瘤微环境的重要贡献者 来推动疾病的发展。脑肿瘤是兴奋性细胞，容易释放/摄取神经递质， 它们的生长，但这种高神经活动尚未在BM中研究，尽管BM受到神经支配。 骨髓细胞有几种神经受体，这表明这些细胞可以很容易地对神经线索做出反应。作为BM 神经支配对于其维持和免疫动员是重要，来自GBM的异常神经活性 改造地下堡垒的方法还没被探索过因此，在GBM模型中使用BM去神经研究，我将评估神经 活性作为骨髓中骨髓偏斜的关键参与者，并将免疫抑制性骨髓细胞募集到骨髓中。 个脑袋阐明神经胶质瘤与骨髓之间通过神经通讯的相互作用提供了一个新的思路。 有机会破坏信号传导，而不必考虑血脑屏障药物 恍惚。