# Study of AR transcriptional network in stem cell model of SBMA

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $394,895

## Abstract

X-linked spinal and bulbar muscular atrophy (also known as SBMA or Kennedy's disease) is a
rare neuromuscular disorder characterized by adult-onset proximal muscle weakness due to
lower motor neuron degeneration. SBMA patients display signs of androgen insensitivity,
including gynecomastia, reduced fertility, and testicular atrophy. SBMA, is caused by a CAG-
polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene and is one member
of a family of nine CAG-polyQ repeat disorders that includes Huntington’s disease. For
decades, research into the basis of neurological disease focused upon the contribution of
neuronal dysfunction to disease pathogenesis. However, over the last ten years, there has been
growing evidence in the motor neuron disease field that challenges the prevailing neurocentric
theory of the etiology of many neurological diseases. . In the case of SBMA, there is increasing
evidence implicating muscle dysfunction as a major component of disease pathogenesis. For
therapeutic purposes, however, different groups have demonstrated successful treatments
targeting either the skeletal muscles or the central nervous system using different SBMA animal
models. Consequently, this lack of consensus in the literature underscores the need for studies
of the SBMA AR-mutation on affected cell types - skeletal muscles and motor neurons - in a
human background. We hypothesized that polyQ mutation cause disruption in AR binding to the
DNA which leads to transcriptional dysregulation that can be pathogenic in motor neurons,
skeletal muscles or both. Therefore, the goal of this proposal is to combine AR genome wide
occupancy and gene expression data sets generated from SBMA and CRISPR engineered
isogenic controls iPSC-derived skeletal muscle and motor neurons. We will then, co-culture the
iPSC-derived skeletal muscles with iPSC-derived motor neurons to modulate the AR targets
identified in the AR transcriptional network and investigate neuromuscular junctions (NMJ) by
analyzing electrophysiological activity of the motor neurons and the skeletal muscles. This work
will advance understanding on the molecular mechanisms of human mutant AR to SBMA
pathogenesis and evaluate the utility of iPSC-derived skeletal muscles and motor neurons tool
to develop SBMA in vitro studies.

## Key facts

- **NIH application ID:** 10184227
- **Project number:** 1R01NS121374-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Helen C Miranda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,895
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10184227

## Citation

> US National Institutes of Health, RePORTER application 10184227, Study of AR transcriptional network in stem cell model of SBMA (1R01NS121374-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10184227. Licensed CC0.

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