# Creatine Transporter Deficiency and Brain Energetics

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $456,966

## Abstract

PROJECT SUMMARY (Description)
Creatine (Cr) and its high-energy product phosphocreatine (PCr) are key components of the phosphagen
system that, along with glycolysis, replenishes ATP to provide the fuels for proper cellular functions. The
human body synthesizes approximately 50% of the daily need for Cr from arginine and glycine using
arginine:glycine amidinotrasnferase (AGAT, in kidney) and guanidinoacetate methyltransferase (GAMT, in
liver), and the other half of Cr is derived from food. While its subcellular localization remains unclear, creatine
transporter (CrT) is essential for building/maintaining the brain Cr concentration in humans, which is clearly
demonstrated in the disease CrT deficiency that was first discovered in 2001. In the absence of CrT (which is
located in the X-chromosome), the afflicted children manifest severe cognitive deficits and near-complete
absence of the brain Cr/PCr on magnetic resonance spectroscopy (MRS). Importantly, unlike patients with Cr
synthesis enzyme mutations, those with CrT deficiency respond poorly to Cr supplement treatment. Hence,
there is a need to determine the functions of CrT and the neuropathological basis of its deficiency in order to
develop effective clinical treatments.
 Based on these results, we hypothesize that the absence of Cr/PCr promotes the AMPK and autophagic
signaling pathways, while suppressing mTOR activity in the brain, leading to dendritic spine dysgenesis and
susceptibility to hypoxic-ischemic injury. Further, CrT mediates the transport of Cr across pericytes and/or the
astroglial end-feet in the brain. Finally, intranasal Cr application can restore the brain Cr/PCr level and correct
neuropathological consequences of CrT deficiency. We will test these hypotheses in three specific aims.
 Aim 1: To determine the functions and sub-cellular location of CrT in the brain.
 Aim 2: To determine the impacts of CrT deficiency on cell signaling and cerebral ischemia.
 Aim 3: To develop treatments of the neuropathological and cognitive deficits in CrT deficiency.

## Key facts

- **NIH application ID:** 9966048
- **Project number:** 5R01NS108763-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Chia-Yi Kuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,966
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966048

## Citation

> US National Institutes of Health, RePORTER application 9966048, Creatine Transporter Deficiency and Brain Energetics (5R01NS108763-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966048. Licensed CC0.

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