Nicotine promotes perineural brain metastasis by activating GABAergic neurons

尼古丁通过激活 GABA 能神经元促进神经周围脑转移

• 批准号: 10572577
• 负责人: Shih-Ying Wu
• 金额: $ 10.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572577
• 关键词: Address; Animal Model; Brain; Brain Neoplasms; Cancer Biology; Cancer Patient; Cells; Clinical; Clinical Trials; Coculture Techniques; Communication; Communities; Data; Data Analyses; Development; Family; Future Generations; GABA Receptor; GABA transporter; Genes; Glean; Goals; Immunologic Surveillance; In Vitro; Incidence; Intake; Laboratories; Leadership; Malignant neoplasm of lung; Mentors; Mentorship; Metabolic; Metabolism; Metastatic malignant neoplasm to brain; MicroRNAs; Microglia; Molecular; Neurons; Nicotine; Pathologic; Pathway interactions; Patients; Phase; Prevention; Prevention strategy; Production; Prognosis; Publishing; Recurrent tumor; Research; Resources; Risk Factors; Role; Shunt Device; Smoker; Smoking; Smoking History; Synapses; System; Techniques; Therapeutic Intervention; Training; Universities; WNT Signaling Pathway; Work; career; cell growth; clinically significant; density; efficacy testing; exosome; experience; forest; gamma-Aminobutyric Acid; improved; in vivo; inhibitor; innovation; lung lesion; member; mortality; mouse model; neoplastic cell; neuronal growth; non-smoker; novel; novel strategies; novel therapeutic intervention; perineural; prevent; skills; synaptogenesis; therapeutically effective; translational cancer research; treatment strategy; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT Patients with brain metastasis of lung cancer have extremely poor prognosis, high mortality rate, and frequent incidence of tumor recurrence. Understanding the pathological mechanism of brain metastasis is urgently needed to develop a novel and effective therapeutic strategy. Published data as well as the results of my own study for brain metastasis of lung cancer indicate that smoking and nicotine significantly increased the incidence and progression of brain metastasis, but the pathological mechanism by which the smoking promotes brain metastasis through modulating brain microenvironment is yet poorly understood. Our preliminary results showed that synaptic formation in brain metastasis region is strongly correlated with poor overall survival of patients with brain metastasis. However, the exact role of neurons in brain metastasis progression remains unclear. The goal of this proposal is to elucidate the mechanism of GABAnergic neuron activation in the brain metastasis in order to develop innovative strategies for the treatment of brain metastasis. I hypothesize that nicotine stimulates microglia to secrete exosomal miR-32-3p which promotes brain metastasis by augmenting GABAergic synaptic formation and hence releasing GABA that serves as metabolic substrate to fuel tumor cell growth. I also hypothesize that inhibiting the GABA transporter of tumor cell suppresses brain metastasis by blocking GABA shunt. In Aim 1, I will clarify the molecular pathway through which nicotine stimulates microglia to secrete exosomal miR32-3p and activates GABAergic neuron. In Aim 2, I will investigate the pathological mechanism by which the activated GABAergic neuron enhances brain metastasis by promoting GABA shunt of tumor cells. Aim 3 is to test the efficacy of inhibitors for GABA transporter on nicotine-stimulated brain metastasis. The K99 phase of the proposed research will be pursued at Wake Forest University (WFU), an interactive cancer biology community, and a wealth of intellectual and technical resources. The training plan, under the mentorship of Dr. Watabe, outlines a comprehensive strategy for acquiring the technical and the professional skills required to complete the proposed research and prepare me for an independent research career. Experienced six members of my mentor team will provide training in new techniques and analyses of data. By taking advantage of Wake Forest‘s exceptional resources for professional development, I will also improve my skills for communication, management, and leadership. The training I obtain at WFU will equip me to lead a laboratory that merges diverse approaches to investigate the mechanisms of initiation and progression to clinically significant brain metastasis and identify innovative strategies for prevention and treatment of brain metastasis.

项目摘要/摘要 肺癌脑转移的患者的预后非常差，死亡率高和频率 肿瘤复发的发生率。急切地了解脑转移的病理机制 需要制定一种新颖有效的治疗策略。发布的数据以及我自己的结果 研究肺癌脑转移的研究表明，吸烟和尼古丁显着增加了 脑转移的发病率和进展，但吸烟的病理机制 通过调节脑微环境来促进脑转移尚未理解。我们的 初步结果表明，脑转移区域的突触形成与较差 脑转移患者的总生存率。但是，神经元在脑转移中的确切作用 进展尚不清楚。该提议的目的是阐明Gabanergic神经元的机制 脑转移的激活，以制定用于治疗脑转移的创新策略。 我假设尼古丁刺激小胶质细胞到促进大脑的秘密外泌体miR-32-3p 通过增强GABA能突触形成，从而释放GABA的转移 基材以燃料肿瘤细胞生长。我还假设抑制肿瘤细胞的GABA转运蛋白 通过阻塞GABA分流来抑制脑转移。在AIM 1中，我将阐明通过 尼古丁会刺激小胶质细胞到秘密外泌体miR32-3p并激活GABA能神经元。在AIM 2中， 我将研究活化的GABA能神经元增强大脑的病理机制 转移通过促进肿瘤细胞的GABA分流。目标3是测试抑制剂对GABA的效率 尼古丁刺激的脑转移的转运蛋白。 拟议的研究的K99阶段将在Wake Forest University（WFU）进行，这是一个互动 癌症生物学社区以及大量的智力和技术资源。培训计划，在 Watabe博士的遗产概述了获取技术和专业人士的全面策略 完成拟议的研究所需的技能并为我做好独立研究职业的准备。 我的导师团队中经验丰富的六名成员将提供有关新技术和数据分析的培训。经过 利用Wake Forest的专业发展资源，我还将改善我的 沟通，管理和领导能力的技能。我在WFU获得的培训将使我领导 合并不同方法的实验室，以研究主动性和发展的机制 临床意义的大脑转移并确定预防和治疗大脑的创新策略 转移。