Decoding hyperexcitability in malignant glioma

项目总结 恶性胶质瘤是一组高级别的脑肿瘤，代表了最常见的 恶性脑瘤。目前的治疗方案包括手术、化疗和 在诊断出最致命的胶质瘤变种后，放射治疗仍有5年存活率， 胶质母细胞瘤(GBM)仍处于停滞状态，不到6%。当新的科学研究继续产生新的 疾病驱动机制，存活率在过去30年中保持不变，突显出 需要新的治疗方法来治疗这些一致致命的疾病。 最近的科学研究表明，恶性胶质瘤形成直接突触电化学。 与瘤外神经元的连接，以维持持续的增殖和迁移。对此的研究 胶质瘤细胞和非肿瘤神经细胞之间复杂的相互作用开启了一条新的科学探究路线 被称为癌症神经科学。鉴于这些神经科学先例的存在，我的博士前 研究建议定义负责突触发生和突触维持的程序是如何 在恶性胶质瘤中的应用和持续。我发现了一种新的蛋白质，免疫球蛋白超家族 成员3(IGSF3)，在子宫神经发育和恶性胶质瘤中均有高表达。我的 使用宫内电穿孔小鼠胶质瘤模型的初步数据显示，IGSF3 过度表达通过增加增殖和降低存活率来推动肿瘤进展。此外， IGSF3过表达促进肿瘤小鼠早发性癫痫发作并选择性增强兴奋性 肿瘤边缘的突触后成分。根据我最初的研究，我假设增加IGSF3 通过增加钾介导的过度兴奋性来推动胶质瘤的进展，从而导致继发性 周围神经回路的突触改变。这种超兴奋性然后反馈到肿瘤 通过增加有丝分裂和迁移信号通路促进肿瘤进展。 我的博士前研究结果让我假设存在异常的电生理 肿瘤细胞内的活动，这也有助于疾病的进展。因此，我的博士后 研究将集中于定义和模拟人基底膜的肿瘤固有电生理活动，以 更好地了解这些网络如何促进疾病进展。这项研究 提案旨在总结之前报道的研究成果和我的初步实验结果 这支持了我的假设和理论基础，并旨在解释我的研究的意义和创新之处 以及我将使用的科学方法和技术，以执行我的科学研究路线。

PROJECT SUMMARY Malignant gliomas are a group of high-grade brain neoplasms that represent the most common form of malignant brain tumors. Current treatment regimens include an amalgamation of surgical, chemotherapeutic and radiation treatments yet 5-year survival rates following diagnosis of the most lethal glioma variant, glioblastoma (GBM) remains stagnant at less than 6%. While new scientific inquiries continue to yield novel disease-driving mechanisms, survival rates have remained unchanged over the past 30 years, highlighting a need for new therapeutic approaches for these uniformly fatal diseases. Recent scientific investigations have revealed that malignant gliomas form direct synaptic electrochemical connections with extratumoral neurons to sustain continued proliferation and migration. The study of this complex interplay between glioma cells and non-tumor neural cells has launched a new line of scientific inquiry known as cancer neuroscience. Given the existence of these neuroscientific precedents, my predoctoral research proposes to define how programs responsible for synaptogenesis and synaptic maintenance are utilized and sustained in malignant glioma. I have identified a novel protein, immunoglobulin superfamily member 3 (IGSF3), with high expression levels in both in utero neurodevelopment and malignant glioma. My preliminary data using an in utero electroporation mouse model of glioma have revealed that IGSF3 overexpression drives tumor progression by increasing proliferation and decreasing survival. Furthermore, overexpression of IGSF3 promotes early-onset seizures in tumor mice and selectively increases excitatory postsynaptic components at the tumor margin. Based on my initial studies, I hypothesize that increased IGSF3 drives glioma progression by increasing potassium-mediated hyperexcitability that leads secondarily to synaptic alterations in the surrounding neuronal circuitry. This hyperexcitability then feeds back to the tumor to promote tumor progression through increased mitogenic and promigratory signaling pathways. The results of my predoctoral studies have led me to hypothesize that there is aberrant electrophysiological activity within tumor cells and that this contributes to disease progression as well. Thus, my postdoctoral studies will focus on defining and modeling tumor-intrinsic electrophysiological activity in human GBM to achieve a better understanding of how these networks contribute to disease progression. This research proposal seeks to summarize previously reported research findings and my preliminary experimental results that support my hypotheses and rationale, and aims to explain the significance and innovation of my study as well as the scientific methodologies and techniques I will utilize in order to execute my lines of scientific inquiry.