# Study of SBMA mutant AR transcriptional network in stem cell-derived motor neurons and skeletal muscle

> **NIH NIH K01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $156,395

## Abstract

SUMMARY
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. Recently, we have identified increased cell death in control motor
neurons subjected to conditioned media from SBMA iPSC-derived skeletal muscles compared to control
derived skeletal muscles. This finding emphasizes the importance of muscle toxicity in SBMA disease
pathogenesis. For therapeutic purposes, however, there is lack of consensus in the literature. Different groups
have been able to demonstrate successful treatments targeting either the skeletal muscle or the central
nervous system using different SBMA animal models. Consequently, there is a need for studies of the SBMA
AR-mutation on the affected cell types, skeletal muscle and motor neurons, in a human background.
Therefore, the applicant, Dr. Helen C. Miranda, is proposing to combine her considerable experience in
stem cell biology and motor neuron disease modeling to a mentorship in functional genomics, to test the
hypothesis that the AR transcriptional network is tissue-specific in SBMA. This project will test this hypothesis
by combining AR genome wide occupancy and gene expression data sets generated from SBMA and isogenic
controls iPSC-derived skeletal muscle and motor neurons. 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. Dr. Miranda is a new Assistant
Professor in the Department of Genetics and the Department of Neuroscience at Case Western Reserve
University. She will devote 75% of her time to research under this award and will supplement her research with
didactic training in genomic and transcriptomic analyses. This training will be comprised of 1) departmental and
university courses, 2) seminars and journal clubs 3) responsible conduct of research courses and 4) national
and international conferences. Dr. Miranda will be mentored by Dr. Anthony Wynshaw-Boris and Dr. Ann
Harris at Case Western Reserve University. These established scientists are both renowned experts in stem
cell biology and functional genomics. Dr. Miranda has met with ea...

## Key facts

- **NIH application ID:** 9953031
- **Project number:** 1K01NS116119-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Helen C Miranda
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,395
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953031

## Citation

> US National Institutes of Health, RePORTER application 9953031, Study of SBMA mutant AR transcriptional network in stem cell-derived motor neurons and skeletal muscle (1K01NS116119-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953031. Licensed CC0.

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