Nicotine promotes perineural brain metastasis by activating GABAergic neurons

项目总结/摘要 肺癌脑转移患者预后极差，死亡率高，且常 肿瘤复发率。了解脑转移瘤的病理机制是当务之急 需要开发一种新的有效的治疗策略。发表的数据以及我自己的结果 对肺癌脑转移研究表明，吸烟和尼古丁显著增加了 脑转移的发病率和进展，但吸烟的病理机制， 通过调节脑微环境促进脑转移的机制尚不清楚。我们 初步结果表明，脑转移区域的突触形成与脑转移不良密切相关。 脑转移患者的总生存率。然而，神经元在脑转移中的确切作用 进展尚不清楚。本研究的目的是阐明GABA能神经元的作用机制， 激活脑转移瘤，以开发治疗脑转移瘤的创新策略。 我假设尼古丁刺激小胶质细胞分泌外泌体miR-32- 3 p， 通过增强GABA能突触的形成，从而释放GABA， 基质来促进肿瘤细胞生长。我还推测，抑制肿瘤细胞的GABA转运蛋白， 通过阻断GABA分流抑制脑转移。在目标1中，我将通过以下方式阐明分子途径： 尼古丁刺激小胶质细胞分泌外泌体miR 32 - 3 p并激活GABA能神经元。在目标2中， 我将研究激活的GABA能神经元增强脑功能的病理机制， 通过促进肿瘤细胞的GABA分流转移。目的3是测试GABA抑制剂的功效 尼古丁刺激的脑转移。 拟议研究的K99阶段将在维克森林大学（WFU）进行，这是一个互动的研究项目。 癌症生物学社区，以及丰富的智力和技术资源。培训计划，根据 渡边博士的指导，概述了一个全面的战略，获得技术和专业 完成拟议研究所需的技能，并为我的独立研究生涯做好准备。 我的导师团队中有六名经验丰富的成员将提供新技术和数据分析方面的培训。通过 利用维克森林的专业发展的特殊资源，我也将提高我的 沟通、管理和领导能力。我在WFU获得的培训将使我能够领导一个 一个实验室，融合了不同的方法来研究启动和发展的机制， 具有临床意义的脑转移，并确定预防和治疗脑转移的创新策略 转移

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.