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

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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.