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 each of her mentors to discuss this project and will continue to meet with them at regular intervals (specified in mentorship letters) during the course of this award. She is expected to produce manuscripts as corresponding or co-corresponding author and be competitive for R-level grants during the course of this award. This project will integrate Dr. Miranda?s current expertise with additional training to develop a well-rounded, independent research program.
This proposal will explore the human stem cell model previously generated by our group for the incurable motor neuron disease: spinal and bulbar muscular atrophy (SBMA). This work will elucidate the transcriptional regulation involved this disease in a human backgroung. The results generated by this study will have direct implications for therapy development in SBMA, and broadly, it will contribute to a new understanding of how skeletal muscle and motor neurons interact to produce neuromuscular diseases.