# Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $588,434

## Abstract

Abstract
Traumatic brain injury (TBI) has a complex neuropathology involving progressive alterations in brain centers
that process cognitive and emotional behaviors and consist of heterogeneous cell populations. The complex
spatiotemporal cell and molecular circuits underlying progressive TBI pathologies that can evolve into other
disorders such as chronic traumatic encephalopathy and posttraumatic stress disorder remain to be
understood. A comprehensive understanding of the molecular mechanisms underlying the complexity of TBI
has been hindered by the lack of effective approaches to examine molecular events in individual brain cells
that drive the overall pathology. We recently conducted a single cell resolution study of the hippocampus at the
acute phase (24hr) of TBI using single cell RNA sequencing (scRNAseq) and revealed cell-type specific
pathways and regulators of TBI. In particular, we found that depression of cell metabolism to be a key
pathogenic component in the hippocampus at the acute phase of TBI. This finding suggests that tracking
metabolic state of cells can be used to address key knowledge gaps on the spatial and time dependent
progression of key pathologic drivers of TBI. Here we propose to test the hypothesis that cell metabolic
regulators determine dynamic and spatial pathogenic pathways of TBI by harnessing the power of modern
high-throughput technologies. We propose a highly integrative team approach to profit from recent advances in
single cell RNA sequencing (scRNAseq) and multiplexed error robust fluorescent in situ hybridization
(MERFISH) along with advanced gene-gene and cell-cell network modeling to inform on targets for intervention
at specific time points or brain sites, a fundamental unsolved question in the TBI field. In Aim 1, we propose to
utilize a unique combination of scRNAseq, MERFISH, and network modeling approaches to assess and
validate the spatial and temporal vulnerability of each cell type to TBI in multiple brain regions at multiple time
points in a data-driven, unbiased manner, which can inform us about hidden regulators of TBI pathogenesis.
We will focus on the spatial and temporal changes in cellular metabolic pathways during TBI progression. Our
preliminary results support that mt-Rnr2, encoding a mitochondrial peptide humanin and involved in cell
metabolism, is a major site- and time-dependent driver of TBI. In Aim 2, we will functionally assess whether
modulating mt-Rnr2 (humanin) has therapeutic potential to mitigate TBI pathology and prevent progression.
We will also explore the cell-type specific mechanisms, especially the role of metabolism, underlying the
actions of humanin. The overall goal of the proposal is to elaborate on an innovative strategy that can offer a
comprehensive mechanistic understanding of the spatiotemporal cell substrates of TBI pathology and uncover
novel targets and mechanisms to redirect the courses of TBI to overcome subsequent neurological disorders.

## Key facts

- **NIH application ID:** 10073315
- **Project number:** 1R01NS117148-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Fernando Gomez-Pinilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,434
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073315

## Citation

> US National Institutes of Health, RePORTER application 10073315, Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution (1R01NS117148-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073315. Licensed CC0.

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