Abstract Concussive injury or mild/moderate TBI (mTBI) accounts for a large majority of the brain injuries in USA and compromises neuronal function and cognitive abilities that can last for years. Neurons that survive the initial insult show a decline in function, and one of the most intriguing aspects of mTBI is that many patients become vulnerable to secondary injury or neurological disorders, which underlying instructions are hiding in alterations of gene programs. The lack of information how TBI alters gene regulatory programs that govern pathogenesis has precluded major advances in strategies to guide TBI therapeutics. Traditional medicine relies on manifestations of symptoms and phenotypes rather than causative factors of the pathology. Instead, alterations in the program of genes are likely causative factors of the pathology and can reveal therapeutic targets that can support precision medicine initiatives. We have recently implemented the use of single-cell genomic analysis to elucidate the impact of TBI on cell types, genes, pathways, and cell-cell interactions that can help inform on novel targets for therapy. Our results from single-cell genomic analysis point to cell metabolism as a driver of mTBI pathogenesis at the cell level and has helped us to prioritize thyroid hormone (important metabolic modulator) as a potential therapeutic agent. The underlying hypothesis is that treatment with thyroid hormone T4 can activate gene regulatory mechanisms that control functionality of circuits in brain regions important for processing of higher order information. Leveraging the expertise of Dr. Xia Yang in genomics and systems biology, and Dr. Fernando Gomez-Pinilla in TBI, we will utilize state-of-the-art parallel single cell sequencing (drop-seq) to assess changes in gene expression in cells forming circuits in brain regions related to cognitive processing. A unique aspect of our project is the implementation of highly sophisticated genomic procedures to understand unsolved questions in the field of neural repair and plasticity and to monitor the efficacy of treatments, using basic concepts of precision medicine. Astrocytes supply energy used by neurons, and they play a crucial role in the incorporation of thyroid hormone from blood into neuronal cells, and according to our preliminary data, astrocytes are highly vulnerable to TBI. We will modulate astrocyte activities to probe the role of astrocytes on circuit reorganization after TBI and on the effects of thyroid hormone. Our studies have the promise to open new avenues to mitigate mTBI pathology based on cell-specific functional aspects of gene regulation, which is also a main premise for precision medicine initiatives.

Narrative We will evaluate the proof of concept that highly sophisticated genomic procedures can be used to guide the efficacy of targeted treatment. We will use single-cell genomics to identify the brain cells most susceptible to brain trauma. We have identified the thyroid hormone transport gene Ttr as one the most affected by TBI, and we propose to target Ttr using T4 treatment, expecting to normalize plasticity and altered gene circuits.