Decoding hyperexcitability in malignant glioma

解码恶性神经胶质瘤的过度兴奋

基本信息

批准号：
10666662
负责人：
Rachel Naomi Curry
金额：
$ 4.77万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666662
关键词：
Acceleration Accounting Activity Cycles Adult Glioma Affect Automobile Driving Back Bar Codes Binding Biochemical Biological Assay Brain Brain Neoplasms Cell Communication Cell Cycle Cell Proliferation Cell secretion Cells Classification Collecting Cell Complex Data Dedications Diagnosis Disease Disease Progression Electrocorticogram Electroencephalography Electrophysiology (science)Electroporation Epilepsy Etiology Event Evolution Feeds Gene Expression Genes Glioblastoma Glioma Goals Human Image Immunoglobulins In Vitro Incidence Individual Investigation Isocitrate Dehydrogenase Label Laboratories Maintenance Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Mediating Methodology Modeling Molecular Molecular Profiling Mus Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurons Neurosciences Operative Surgical Procedures Pathway interactions Patients Postdoctoral Fellow Potassium Potassium Channel Process Proliferating Property Proteins Proteomics Radiation therapy Reporting Research Research Project Grants Research Proposals Role Sampling Scientific Inquiry Secondary to Seizures Signal Pathway Slice Survival Rate Synapses System Techniques Therapeutic Time Transposase Treatment Protocols Tumor Biology Tumor Promotion Variant career early onset experimental study gain of function glioma cell line in utero in vivo innovation interest loss of function member migration mouse model multidisciplinary mutant mutational status neoplastic cell neurodevelopment neuronal circuitry neuronal tumor novel novel therapeutic intervention overexpression postsynaptic pre-doctoral precision medicine programs single-cell RNA sequencing standard of care survival outcome synaptogenesis technological innovation transcriptome sequencing transcriptomics tumor tumor progression

项目摘要

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.

项目概要恶性胶质瘤是一组高级别脑肿瘤，代表最常见的形式恶性脑肿瘤。目前的治疗方案包括手术、化疗相结合和放射治疗，但诊断出最致命的神经胶质瘤变异后的 5 年生存率，胶质母细胞瘤 (GBM) 的比例仍停滞在 6% 以下。虽然新的科学探究不断产生新颖的成果疾病驱动机制，生存率在过去 30 年中保持不变，突显了需要新的治疗方法来治疗这些致命的疾病。最近的科学研究表明，恶性神经胶质瘤形成直接突触电化学与肿瘤外神经元的连接以维持持续的增殖和迁移。本研究的神经胶质瘤细胞和非肿瘤神经细胞之间复杂的相互作用启动了新的科学探究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如何在恶性神经胶质瘤中使用和维持。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都有高表达水平。我的使用神经胶质瘤子宫内电穿孔小鼠模型的初步数据表明 IGSF3 过度表达通过增加增殖和降低存活率来驱动肿瘤进展。此外， IGSF3 过度表达促进肿瘤小鼠早发性癫痫发作并选择性增加兴奋性肿瘤边缘的突触后成分。根据我的初步研究，我假设 IGSF3 增加通过增加钾介导的过度兴奋来驱动神经胶质瘤进展，从而导致周围神经元回路的突触改变。这种过度兴奋然后反馈给肿瘤通过增加有丝分裂和前迁移信号通路促进肿瘤进展。我的博士前研究结果使我推测存在异常的电生理学肿瘤细胞内的活性，这也有助于疾病进展。于是，我的博士后研究将集中于定义和模拟人类 GBM 中肿瘤固有的电生理活动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结果和我的初步实验结果支持我的假设和基本原理，旨在解释我的研究的意义和创新以及我将用来执行我的科学探究的科学方法和技术。