# Thyroid Hormone Action

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $385,000

## Abstract

PROJECT SUMMARY
The long-term goal of this research is to improve our understanding of thyroid hormone action using ligand-
based, small molecule approaches. Thyroid hormone has important actions related to health and disease in all
tissues of the body including the central nervous system (CNS) where thyroid hormone plays a key role in
regulating brain development and maintaining specialized cell populations and structures such as myelin.
Compared to thyroid hormone's actions in the periphery, much less is known at the molecular and mechanistic
level about its actions in the brain, and increased knowledge of thyroid hormone brain actions would be useful
for developing new therapeutics for CNS disorders that intersect with thyroid hormone action including multiple
sclerosis and other demyelinating diseases, and Allan-Herndon-Dudley Syndrome and other disorders
involving unbalanced thyroid hormone levels in the CNS. A major limitation from a ligand/small molecule
perspective is that there are currently no thyroid hormone receptor (TR) ligands, endogenous or synthetic, that
distribute preferentially to the CNS from a systemically administered dose. As such, it is difficult to separate
CNS from peripheral hormone effects and the lack of a therapeutic window separating desired therapeutic
CNS actions from undesired systemic toxic actions is emblematic of this issue. The proposed research plan
seeks to address this problem by devising and validating a pro-drug based strategy that will selectively deliver
a TR ligand across the blood-brain-barrier (BBB) and into the CNS while minimizing the TR ligand exposure in
circulation and peripheral organs and tissues. This selective increase in CNS vs. peripheral exposure should
result in an increased window separating TR driven CNS effects from those in the periphery. The pro-drug
design is based on amino-ester derivatives of TR ligands and these novel compounds will be synthesized and
evaluated for CNS uptake in Specific Aim 1. CNS-selective TR activation will be assayed in Specific Aim 2
through a series of functional assays involving TR in the CNS and periphery. In Specific Aim 3, the
mechanism of BBB penetration, pro-drug activation, pro-drug pharmacokinetics, and pro-drug influence on free
drug in the CNS will be evaluated. This research will enable the creation of new CNS-selective TR ligands that
will be useful as research tools and potentially serve as prototypes for new thyroid hormone-based
therapeutics for CNS disorders.

## Key facts

- **NIH application ID:** 9857010
- **Project number:** 5R01DK052798-21
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** THOMAS Sterling SCANLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 1997-09-30 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857010

## Citation

> US National Institutes of Health, RePORTER application 9857010, Thyroid Hormone Action (5R01DK052798-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857010. Licensed CC0.

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