Understanding the Role of Astrocytes and Glutamate Dynamics in Promoting Neuroprotection and Remyelination Using PET and Metabolic MR Imaging
Abstract
The proposed work will address the Focus Area Central Nervous System Regenerative Potential in Demyelinating Conditions. Multiple sclerosis (MS) is a disease characterized by damage to the myelin sheaths and axonal injury, taking place in an inflammatory environment. These demyelinating events may be followed by spontaneous recovery, however, they most often lead to axonal loss and permanent damage that is responsible for increased MS disability. Glutamate, a signaling molecule that is tightly regulated under normal conditions, has been suggested as a mediator between inflammation and neuronal death. Because impairment in glutamate levels has been observed in MS, restoring glutamate homeostasis appears as a promising target to provide axonal protection and accelerate repair. To date, our understanding of mechanisms that drive glutamate imbalance in lesions have been limited by the lack of noninvasive imaging methods. In this project, we propose to develop and validate innovative noninvasive magnetic resonance (MR) and positron emission tomography (PET) imaging tools to evaluate in situ real time glutamate metabolism. Specifically, we propose to use a novel PET imaging agent to image a major transporter of glutamate in the brain, which is expressed by astrocytes. Next, to measure glutamate production, we propose to use hyperpolarized carbon-13 MR metabolic imaging, which is a novel method allowing the evaluation of metabolic fluxes in real time on a conventional MR system. To validate these imaging agents, we have chosen two well-described MS mouse models presenting brain demyelination and neuroinflammation. These two models differ by their capability to recover following the demyelinating event. We propose to perform a series of measurements within the same subject to evaluate changes in glutamate transport and production during spontaneous recovery, or following the administration of clinically relevant therapies that promote remyelination and recovery. Upon successful completion of this project, we will validate innovative PET and MR translational imaging approaches to provide novel technical capabilities to assess therapy responses and help understand underlying mechanisms involved in glutamate level regulation, axonal protection and repair. Importantly, both agents proposed in this application (2-13Cpyruvate and 18FFFAA) are already Food and Drug Administration (FDA)-approved for human use. 2-13Cpyruvate has already been successfully applied to measure normal brain metabolism, and 18FFFAA is currently applied in a first-in-human study at our institution. Consequently, promising outcomes from this project would provide a strong rationale for their immediate use in clinical settings to assess disease activity, progression, and recovery. This work will potentially benefit a large number of relapsing-remitting MS and secondary-progressive MS patients, who may present glutamate imbalance. This will contribute to advance precision medicine and potentially aid in the design and evaluation of novel treatments targeting glutamate metabolism, with the aim to ultimately lead to better clinical outcomes and patient quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210991
Entities
People
- Caroline Guglielmetti
Organizations
- United States Army
- University of California, San Francisco