# TR2 nuclear receptor in vitamin A signaling

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $466,114

## Abstract

Project Summary
The grant “TR2 nuclear receptor in vitamin A signaling” (since 08/01/99) was initiated from studying retinoic
acid (RA) signaling using an embryonic stem cell-specific orphan receptor TR2’s (NR2C1) as a model to
understand RA’s action in developmental regulation. The long-term goal is to comprehensively understand RA
signaling pathways in health and diseases. Results first established RA’s activity in chromatin-remodeling via
RA receptors (RARs), Retinoid X receptors (RXRs) and TR2. In 2008, we reported a then-mysterious effect of
RA that did not involve RAR/RXR - it occurred rapidly in the cytoplasm to modulate ERK signaling, and thus
was proposed as “non-canonical”. Previous proposal (05/1/2017-04/30/2022) aimed to i) identify the mediator
of this non-canonical activity of RA in modulating ERK signaling and synthetic RA-like ligands specific to this
pathway, and ii) determine the physiological relevance. Results (published in 14 papers) have established
Cellular Retinoic Acid Binding Protein 1 (CRABP1) as the mediator, characterized RA-CRABP1-RAF-MEK-
ERK signaling pathway and CRABP1 ligands specific to this pathway, and revealed physiological relevance in
maintaining neuron stem cell pool, adiposity and inflammation, all involving CRABP1-ERK regulation. Recently,
a second signaling pathway also directly modulated by CRABP1 was uncovered, calcium/calmodulin-
dependent protein kinase II (CaMKII), but in a different physiological context - excitable cells requiring tight
regulation of CaMKII such as motor neurons (MNs) and cardiomyocytes. The principal hypothesis is, RA-
CRABP1 signalosomes form in specific cellular environments to provide timely (rapid) modulatory
mechanisms ensuring homeostatic propagation of intracellular signals that are critical to the
survival/function of the cells. Pertinent to CRABP1-CaMKII, our recent data show that CRABP1 is highly
expressed in MNs, and CRABP1 knockout (CKO) mice spontaneously develop age-dependent motor deficit
resembling motor symptoms of MN degenerative disease Amyotrophic Lateral Sclerosis (ALS), preceded by
morphological, structural, and functional deterioration of MNs and neuromuscular junctions (NMJs). We thus
engineered a sequenced MN-muscle co-differentiation system on custom-fabricated Hydrogel to generate an
in vitro, functional 3D NMJ model for molecular studies. Two aims are to i) dissect molecular mechanisms
of RA-CRABP1-CaMKII signalsome action in NMJ and identify CRABP1 ligands specific to this
pathway, and ii) determine the physiological action of RA-CRABP1-CaMKII signaling and its disease
relevance/therapeutic applications. Aim 1 will employ engineered 3D NMJ model to dissect physiologically
relevant signaling pathways and molecular mechanisms. Aim 2 will distinguish “non-canonical” from
“canonical” activity of RA by comparing CRABP1 ligands and RA in maintaining healthy NMJs, and determine
the therapeutic potential of targeting CRABP1 to improve motor function.

## Key facts

- **NIH application ID:** 10818552
- **Project number:** 5R01NS132277-21
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Li-Na Wei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,114
- **Award type:** 5
- **Project period:** 1999-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818552

## Citation

> US National Institutes of Health, RePORTER application 10818552, TR2 nuclear receptor in vitamin A signaling (5R01NS132277-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10818552. Licensed CC0.

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