Uncovering New Therapeutics and Neuroprotective Mechanisms for TBI
Abstract
Objectives and Rationale Every year, approximately 1.7 million Americans sustain a traumatic brain injury (TBI) of varying severity and one-sixth of those injuries results in hospital admission. Military personnel are at high risk for TBI – since 2000, over 300,000 Service members were diagnosed with TBI. TBI often results in complex symptoms that affect a patient’s physical, cognitive, emotional, and social well-being. Sleep disorders are highly prevalent in military personnel with TBI, where 97% of patients who developed TBI during military operations also had sleep complaints. Sleep problems after TBI, especially reduced sleep efficiency and increased sleep latency, are also particularly prevalent in children and elderly patients. At the same time, there is no good treatment available for TBI and its related sleep disorders. Promising drug treatments, including Progesterone and Tirilazad, failed in Phase 3 clinical trials. Part of the problem is that TBI is an incredibly complex disorder, where large changes in gene expression occur on different timescales (ranging from seconds to months) after injury. These molecular cascades include a broad-spectrum immune response that has both beneficial and detrimental effects. This also means that there are hundreds or thousands of potential targets for pharmacological intervention. Testing all of these is not feasible in existing rodent models of TBI, for practical and ethical reasons. Instead, a high-throughput model organism is needed that is similar enough to man, yet easy to keep, easy to manipulate on a genetic level, and susceptible to TBI. For our 2015 Peer Reviewed Medical Research Program (PRMRP) award, we developed a Drosophila model for TBI to fit this niche. Our TBI model has all the TBI symptoms found in man – increased mortality, altered gene expression, a strong immune response, and behavioral symptoms that include sleep impairments. The fruit fly brain is very different from the human brain, yet it operates on the same principles – the brain is compartmentalized, where different regions fulfill different functions, using neurotransmitters that are highly similar to those found in mammals. As such, Drosophila has a fruitful history as model organism to study neurodegeneration, sleep and circadian rhythms, learning and memory, development and immunity. The main reason for this success is the wealth of genetic tools that are constantly being developed that allows researchers to manipulate expression of single genes in discrete tissues and study how this affects biological processes. Here, we’ll use these tools to silence genes that change expression after TBI – identified in our 2015 PRMRP project – and test how this affects TBI survival and sleep fragmentation. This will allow us to disentangle beneficial from detrimental responses. If silencing a gene improves TBI outcomes, it is a viable target for intervention strategies. Likewise, if silencing a gene exacerbates TBI outcomes, it is likely to be part of a neuroprotective pathway that can potentially be stimulated. Besides using our genetic approach, we will also use Drosophila’s physiological similarity to man to test a library of FDA-approved drugs for their ability to improve outcomes after TBI. Drosophila has a long history of being used as a first-line screening model in drug discovery and it responds to many high-value pharmaceuticals (including sleep and wake promoting drugs) that similarly affect flies and man. To test their effect on TBI symptoms, we will induce TBI and then place flies on drug-laced food for 7 days, simultaneously monitoring sleep and survival. Topic Area: Sleep Disorders - Research on the precision diagnosis and/or treatment of sleep disorders, especially following TBI. Applicability and Impact Beneficiaries: TBI is the leading cause of death and disability worldwide. Within the U.S., it affects 1.7 million civilians annually as well many memb
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010211
Entities
People
- Ravi Allada
Organizations
- Northwestern University
- United States Army