CAG length–dependent AR dysregulation in SBMA: Investigation of isogenic iPSC-derived neuromuscular system
Summary Description
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, is a rare inherited disorder that causes progressive muscle weakness, difficulty speaking and swallowing, and reduced mobility. It primarily affects men and is caused by a mutation in the androgen receptor (AR) gene, which responds to the male hormone, testosterone. This mutation leads to an abnormal AR protein that disrupts the normal function of both nerve and muscle cells. SBMA has traditionally been viewed as a disease of motor neurons, the nerve cells that control muscle movement. However, emerging research suggests that skeletal muscle itself may play a more central role in the disease than previously thought. This shift in understanding opens the door to new treatment strategies that focus on protecting or repairing muscle tissue. This project will explore how different lengths of the AR gene mutation (known as CAG repeats) affect both muscle and motor neuron function. Using stem cells derived from patients, we will create muscle and motor neurons in the lab and study how they behave with various repeat lengths. We will analyze changes in gene activity, muscle strength, and how effectively motor neurons form connections with muscle cells. By uncovering how muscle contributes to SBMA, this research may lead to more effective therapies, particularly those targeting muscle, which is more accessible for treatment. It may also provide insights into other disorders caused by similar genetic mutations, ultimately benefiting a broader group of patients.
Bio
Caroline Rodrigues, Ph.D, is a scientist with expertise in stem cell biology, molecular disease mechanisms, and human iPSC-based modeling. She received her PhD in Molecular and Morphofunctional Biology from the University of Campinas (Unicamp) in Brazil, where she investigated the pathophysiology of schizophrenia using animal models and patient-derived iPSCs. During her doctoral training, she also gained experience in cellular neuroscience at the Max Planck Institute in Göttingen, where she adapted protocols for isolating synaptic vesicles from iPSC-derived neurons.
Caroline is currently a postdoctoral researcher in the Miranda Lab at Case Western Reserve University, where she studies SBMA using advanced iPSC-based systems. Her work includes generating an isogenic CAG-repeat iPSC panel and developing a functional neuromuscular junction co-culture platform to investigate how androgen receptor expansions affect muscle tissue, motor neurons, and neuromuscular junction physiology.
