Monosynaptic tracing defines circuit connectivity of human high-grade glioma in the adult mouse brain

Ended Project Grant Awarded Last action

Award ID
F31NS137664
Recipient
Awarding agency
Obligated
$282,977

Award facts

Completion date
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
My long-term career aspiration is to become a physician-scientist committed to bringing novel brain tumor therapies from bench to bedside by leading an independent basic science research group. This proposal is a first step in achieving this goal by providing crucial support for an integrated neuroscience/cancer biology-based training plan in the context of brain tumor research at the perelman school of medicine, university of pennsylvania. Glioblastoma is a universally fatal brain cancer that functionally integrates into the normal neural circuitry. IT has been reported that neuronal activity drives tumor progression via glutamatergic synapses onto tumor cells and, in parallel, glioblastoma cells alter neuronal excitability, remodel neural circuits, and impair cognitive function. However, little is known regarding the cellular diversity and circuit architecture of neurons that are connected with tumor cells. Understanding the anatomic and cell type distribution of these connected neurons may reveal unique functional roles of select neuronal subsets in glioma pathogenesis. We hypothesize that glioblastoma receives functional synapses from both local and long-range neuronal projections, consisting of not only glutamatergic but also neuromodulatory inputs. In the normal brain, neuromodulatory inputs project diffusely throughout the brain and play an important role in modulating neuronal excitability, and thus may also function in regulating glioma. In this proposal, we seek to define the glioblastoma connectome using monosynaptic rabies virus (RBV) for retrograde trans-synaptic tracing and monosynaptic herpes simplex virus (HSV) for anterograde trans-synaptic tracing in a xenograft mouse model. In aim 1, we will utilize an in vivo model to map the whole-brain inputs onto glioblastoma by transplanting patient-derived glioblastoma organoids (gbos) to various clinically relevant brain regions in immunodeficient mice. Preliminary studies revealed labeling of diverse neuronal subtypes in various brain regions, and, in particular, basal forebrain cholinergic neurons projecting to transplanted glioblastoma cells in both cortical and subcortical regions. We will confirm cholinergic inputs with HSV-based anterograde trans-synaptic tracing as well as electrophysiological recordings. In aim 2, we will study the functional significance of these cholinergic neuromodulatory inputs onto glioblastoma by performing calcium imaging and single-cell RNA sequencing of glioblastoma organoids treated with acetylcholine as well as assess the impact of acetylcholine on tumor cell invasion in vitro and in vivo. We believe that project outcomes will elucidate the complex brain-wide interactions between tumor cells and diverse neuronal populations and investigate the significance of cholinergic inputs in glioma disease progression, thereby providing novel therapeutic avenues for glioblastoma.

Transactions

Action Obligated Date
Amendment -$11,995
Amendment $564
Amendment $564
Amendment $48,974
Amendment $48,974
Amendment $48,974
Amendment $48,974
Amendment $48,974
Amendment $0
Amendment $0
Original award $48,974
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Quick answers

Who received award F31NS137664?

F31NS137664 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on October 29, 2024.

How much is award F31NS137664 worth?

$282,977 has been obligated on F31NS137664.

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