# A Mechanistic Foundation for the Iron Homeostasis Impacts and Neurotrophic Activity of trans-Banglene

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $385,968

## Abstract

Project Summary/Abstract
Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease, constitute one of
the greatest challenges in modern therapeutic development due to an inadequate understanding of the
interplay of pro- and anti-apoptotic feedback mechanisms operative in the progression of these diseases. This
inadequate understanding is in part due to a lack of practical (crosses blood-brain-barrier, well-studied
mechanism of action) biochemical tools to modulate and effect related cellular processes, such as neurotrophic
responses (pro-survival, pro-growth, and pro-differentation responses), and metal ion homeostasis levels,
which are both significantly perturbed in neurodegenerative contexts.
 The Williams lab and Epp lab propose to evaluate the mechanism and pathological impacts of a non-peptide
small molecule, called trans-banglene (t-BG), which has demonstrated neurotrophic effects in cell culture,
primary neurons and mouse models of neurodegeneration, is orally bioavailable, and also has recently been
shown by the Williams lab to alter iron-binding proteins in PC 12 cells. This combined impact on neurotrophic
responses and iron homeostasis makes t-BG well suited to provide insight into the interplay between these two
cellular response mechanisms. However, a cellular target and mechanism of action is not yet known for t-BG.
 The following proposal outlines work to 1) identify the cell recognition/binding partner and localization upon
binding, 2) characterize t-BG treatment impacts on known neurotrophic signal transduction pathways, iron
localization, and lipid oxidation profile in cells and tissues and 3) to evaluate impacts on neuronal morphology,
plasticity and neurogenesis in AD mouse models. The interdisciplinary setting of the Williams lab enables both
synthetic access to derivatives of this molecular scaffold as well as cell response data from biochemical assays
of their activity. The Epp lab will concurrently validate mechanistic impacts in hAPOE4 knock-in mouse tissues
and measure changes in neurogenesis/neuron structure.
 Importantly, these mechanistic studies will improve understanding of the differential drivers of neurotrophic
effects and iron homeostasis. Once mechanism of action is determined, and validated in mouse models, this
orally bioavailable molecular tool can be broadly employed in the biomedical community to study inhibition of
neurodegenerative disease progression, helping to create the foundation for new medicinal strategies. Further,
once a cellular target is established, future work will use structural information regarding binding mode to inform
optimization studies that increase potency and drug-like characteristics for t-BG, improving its utility and
facilitating drug development investigations.

## Key facts

- **NIH application ID:** 10984777
- **Project number:** 1R21AG083334-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Jonathan Richard Epp
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,968
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984777

## Citation

> US National Institutes of Health, RePORTER application 10984777, A Mechanistic Foundation for the Iron Homeostasis Impacts and Neurotrophic Activity of trans-Banglene (1R21AG083334-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984777. Licensed CC0.

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