Targeting Inflammatory Astrocyte Reactivity in Mild Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) is a leading cause of mortality and disability in military and civilian populations. For Service Members and Veterans, TBI has become the signature wound and a significant health issue during times of both peace and war. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for 80% of TBI cases. mTBI is often recurrent (termed repetitive mTBI) for individuals engaged in military operations and in contact sports. Repetitive mTBI is associated with more severe and protracted cognitive, motor, and behavioral complications. Among them, cognitive impairment (when a person has trouble remembering, learning new things, concentrating, or making decisions) is one of the most common, most disabling, and longest-lasting symptoms, because it is a substantial source of disability that destroys a Veteran s productivity and quality of life. Currently there is no effective treatment available to improve cognitive function, largely due to the fact that our understanding of the injury mechanisms is still incomplete. Animal models play crucial roles in understanding the injury mechanisms and developing treatments of human TBI. This application targets this urgent need to develop a unique treatment for mTBI recovery and cognitive impairment. The goal of this proposal is to develop a mechanism-based therapy targeting astrocytes, the most abundant and star-like cell type in the brain. Astrocytes are multifunctional cells that react to brain insults and are a key determinant of TBI outcome. Astrocytes’ reaction can have both beneficial and harmful effects on TBI outcome, and reducing their harmful effects will promote TBI recovery and improve brain function. Astrocytes represent one of the most intriguing opportunities to tackle cognitive impairment. In our recent work, we identified a novel gene that promotes the formation of harmful and toxic astrocytes, providing a unique avenue for therapeutic intervention. Accordingly, we show that targeting this gene with genetic or pharmacological approaches greatly improves cognitive function in an established, highly reproducible mouse model of repetitive mTBI. This gene has not been studied in astrocytes and its function in promoting formation of harmful astrocytes in completely novel. In this application, we propose to first identify the mechanism of action for the gene activity in astrocytes. We will employ the genetic approach to target this gene and investigate how its activation contributes to brain injury and cognitive deficits. We will then use a pharmacological inhibitor to assess its effect on functional recovery in mice with brain injury. While the genetic targeting approach has an advantage of being cell type-specific and can provide us unique insight into the mechanistic basis of astrocyte action in TBI, pharmacological agents have the potential for translation to clinical testing. In summary, this application aims to tackle cognitive impairment, a common and disabling symptom that TBI survivors often experience. When completed, results from the proposed research will inform us how astrocytes contribute to brain injury and cognitive impairment. They will also provide strong evidence of developing therapeutic strategies targeting this gene to support TBI recovery and cognitive improvement in humans. Together, our results will provide a strong foundation to translate our findings to clinical trials by developing similar or identical agents to the one tested in the animal subjects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310879
Entities
People
- Jian Luo
Organizations
- Palo Alto Veterans Institute for Research
- United States Army