# Novel Regenerative Treatment of TBI and Post TBI Depression

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

As soldiers are returning from wars around the globe, traumatic brain injury (TBI) has been reported
among veterans. Brain structural damage of different degrees and functional/behavioral deficits such
as post-traumatic stress disorder (PTSD) including post-TBI depression (PTD) are frequently seen
among these patients. So far, there is basically no effective treatment for acute TBI or chronic
patients. In recent years, cell-based therapy provides an attractive and coherent approach in
regenerative medicine. Based on the latest advancement and our preliminary data, we propose a
novel delayed treatment by directly converting endogenous astrocytes accumulated around the injury
site into "induced neurons (iNs)" in the chronic phase after TBI. In a mild/moderate TBI mouse model,
the direct reprogramming gene NeuroD1 (ND1) that targets reactive astrocytes will be expressed in
the peri-contusion region by lentiviral injection. We hypothesize that the intra-lineage direct
reprogramming provides a viable endogenous source of new neurons by leveraging existing
proliferative astrocytes after TBI and helps to prevent the development of PTD (Specific Aim 1). We
propose that the reprogramming gene expression will effectively reduce gliosis or glial scar formation
during the chronic phase after TBI, which will lessen physical and chemical barriers for regeneration
and significantly facilitate axonal outgrowth and other regenerative activities (Aim 2). It is further
hypothesized that combined rehabilitation of treadmill exercise will improve ND1-induced gene
regulation, post-TBI tissue repair and functional activities (Aim 3). We propose that, in the combination
therapy, iNs arisen within the host tissue enriched by up-regulated genes such as BDNF and oxytocin
are conducive to integration with existing neural networks. Our preliminary data demonstrate the
feasibility of converting astrocytes into mature neurons, increased regenerative/behavioral genes, and
improved psychological behaviors chronically after TBI. The goal of this investigation is to
demonstrate and develop an effective treatment for veteran patients with TBI-related PTD.

## Key facts

- **NIH application ID:** 10060751
- **Project number:** 5I01RX002473-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Shan P. Yu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10060751

## Citation

> US National Institutes of Health, RePORTER application 10060751, Novel Regenerative Treatment of TBI and Post TBI Depression (5I01RX002473-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10060751. Licensed CC0.

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