Intratumoral functional connectivity with implications on synaptogenesis and aphasia recovery in adult astrocytic WHO II-III glioma

项目总结： 目前有超过70万美国人患有胶质瘤，每年有65名新患者被诊断出来 天。影响生存的因素包括患者的年龄、WHO分级和肿瘤切除的程度。 越来越多地了解语言、认知和沟通能力等功能状态 会影响寿命。虽然一些患者的生存时间很短，但许多人患有世卫组织II级和III级肿瘤 而有利的遗传学将持续20年或更长时间。在整个存活期内，超过70%的患者 体验降低生活质量和生存的功能障碍。这改变了研究和 除了生存之外的临床问题，包括功能结果。我研究的根本目的是 该计划的目的是研究胶质瘤与功能认知网络的双向机制。 临床前文献中有强有力的证据表明神经元活动影响肿瘤进展，但这是 没有从人类的功能能力上进行研究。 关于神经胶质瘤影响功能认知网络的机制，人们知之甚少。为 例如，周语语言网络中语言的精确组织是高度可变的，并且 是什么使某些区域在功能上相关，其背后的细胞机制仍然未知。在功能上 相关区域(由直接皮质刺激确定)增加了与 周围的大脑。最近有研究表明，胶质瘤中不同的星形胶质细胞亚群起到了作用。 对于突触发生，然而它们在肿瘤内的组织和在人类中的功能意义仍然存在 未知。因此，神经胶质瘤与神经的相互作用可能部分由突触源性胶质瘤细胞介导。 可能是这些联系背后的推动力，并在具有高功能的区域内共同本地化 连通性。在这项研究提案中，我将研究优势半球内的功能连接 世界卫生组织II-III星形细胞胶质瘤确定突触源性胶质瘤细胞是否在 功能连通性提升的区域。这项建议中的实验结果将提供更敏锐的 更准确地解释成人胶质瘤中的突触形成如何有助于失语症的恢复。这些 在加州大学旧金山分校稳健的学术环境中进行的实验 涵盖神经回路动力学和神经胶质瘤生物学的科学和教育目标。 此外，他们将为我的培训计划做出贡献，该计划将重点放在建立神经方面的能力 电路生理学，2)失语症康复的神经生物学，3)人类受试者测试，以及4)设计 最终将使我的假说得到临床验证的临床试验。我的培训计划的目标是 为了进一步提高我的神经肿瘤学翻译能力，成为一名R01资助的独立科学家 通过一个研究项目，重点研究了神经胶质瘤影响认知的机制。

PROJECT SUMMARY: Over 700,000 Americans are currently living with a glioma and 65 new patients are diagnosed every day. Factors influencing survival include patient age, WHO grade, and extent of tumor resection, however it is increasingly understood that functional status such as language, cognition, and the ability to communicate impacts longevity. While the survival time of some patients is short, many with WHO grade II and III tumors and favorable genetics will survive for 20 years or longer. Throughout this survival period, over 70% of patients experience functional disabilities that reduce quality of life and survival. This has shifted both research and clinical questions beyond survival to include functional outcomes. The fundamental goal of my research program is to study the bidirectional mechanisms by which gliomas interface with functional cognitive networks. There is strong evidence in the preclinical literature that neuronal activity impacts tumor progression, but this is unstudied from a functional capacity in humans. Little is known about the mechanisms by which gliomas affect functional cognitive networks. For example, the precise organization of language within the perisylvian language network is highly variable and the cellular mechanism behind what makes some areas functionally relevant remains unknown. Functionally relevant regions (as determined by direct cortical stimulation) have increased functional connectivity with surrounding brain. It has been shown recently that distinct astrocyte subpopulations within gliomas contribute to synaptogenesis, however their organization within the tumor and functional significance in humans remains unknown. It is therefore possible that glioma-neural interactions in part mediated by synaptogenic glioma cells may be a driving force behind these connections and co-localize within regions with high functional connectivity. In this research proposal I will study functional connectivity within dominant hemisphere perisylvian WHO II-III astrocytic gliomas to determine whether synaptogenic glioma cells are enriched within regions of elevated functional connectivity. The results of the experiments in this proposal will offer a sharper and more accurate account of how synaptogenesis in adult gliomas contributes to aphasia recovery. These experiments conducted in the robust academic environment of University of California San Francisco and encompass scientific and education aims covering both neuro circuit dynamics and glioma biology. Furthermore, they will contribute to my training plan, which will focus on establishing competence in 1) neural circuit physiology, 2) the neurobiology of aphasia recovery, 3) human subject testing, and 4) design of the clinical trial trials that will ultimately enable clinical validation of my hypothesis. The aims of my training plan are to further my training in translational neuro-oncology toward becoming an independent R01-funded scientist with a research program focused the mechanisms by which gliomas influence cognition.