# Kinetic Barriers of Transdifferentiation

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2020 · —

## Abstract

Abstract
 Dysfunction of the serotonergic system is critically involved in a diverse range of
diseases, which accumulatively affect at least 20% of the population. In our preliminary studies,
we identified transcription factors that converted human fibroblasts to induced serotonergic
(i5HT) neurons. The efficiency was significantly increased by p53 knockdown and appropriate
cell culture conditions. At day 12 of reprogramming, 50% of the cells were Tuj1+ neurons and
25% were 5HT+ neurons. This epigenetic reprogramming was dependent on Tet proteins, a
family of three DNA hydroxylases that critically regulate the epigenome. Knocking down each of
the Tet genes abolished the epigenetic conversion. We hypothesize that p53, Tet proteins, and
appropriate extracellular environment are critical for the direct conversion human fibroblasts to
i5HT neurons. To test this hypothesis, we will identify the optimal transcription factor
combinations, investigate how p53 knockdown induces Tet genes, and study how Tet proteins
and reprogramming factors impact on the transcriptome to facilitate the transdifferentiation of
human fibroblasts to i5HT neurons. We will also examine the impact of cell culture environment
on the conversion and assess the survival and function of i5HT neurons transplanted in rat
brains. The proposal will develop a robust method for the generation of patient-specific and
subtype-specific i5HT neurons, which would enable basic research and drug discovery on
serotonin-related disorders.

## Key facts

- **NIH application ID:** 9898300
- **Project number:** 5I01BX002452-07
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** JIAN FENG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898300

## Citation

> US National Institutes of Health, RePORTER application 9898300, Kinetic Barriers of Transdifferentiation (5I01BX002452-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898300. Licensed CC0.

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