Investigating differences in polyQ-AR genomic activity leading to muscle atrophy in SBMA: At the heart of Kennedy’s Disease
Summary - $75,000. Anastasia Gromova, University of California, Irvine. Recipient of the 2023 Waite-Griffin SBMA Fellowship Reward. Investigating differences in polyQ-AR genomic activity leading to muscle atrophy in SBMA: At the heart of Kennedy’s Disease (KD) pathogenesis is the potent reduction of core muscle genes that encode contractile proteins, unsurprisingly leading to muscle loss, but we do not yet fully understand how polyglutamine-expanded AR (polyQ-AR) causes this. We and others have observed that in muscle of KD mouse models, the activity of a transcription factor critically important for sustained muscle gene expression called MEF2 becomes highly defective. MRF4, another muscle transcription factor, is known to repress the activity of MEF2 to prevent uncontrolled muscle growth, and knockdown of MRF4 in muscle cells grown in a dish causes a reduction in polyQ-AR protein levels. This study will determine if MRF4 is involved in KD muscle loss by assessing if disease course is altered in model mice that lack the MRF4 gene. We will also apply cutting-edge genomic techniques to investigate where in the genome of mouse muscle AR and polyQ-AR is binding, and whether those patterns are affected by loss of MRF4. These experiments will provide critical insight into how AR’s interaction with the genome of fully mature, physiological muscle cells is altered by the polyglutamine expansion and whether MRF4 mediates this alteration.
Bio: Anastasia has been studying KD since 2016, when she joined Dr. Albert La Spada’s lab as a first year Biomedical Sciences graduate student at UC San Diego. Coming from a research background in skeletal muscle regeneration and muscular dystrophy, she was instantly awestruck by a 2015 lecture by Dr. Constanza Cortes, then a postdoc in the La Spada lab, in which Dr. Cortes presented their findings on the requirement of polyglutamine-expanded AR expression in skeletal muscle as being necessary for both muscle and motor neuron degeneration. Now a postdoc herself at UC Irvine, she continues to be strongly committed to solving the paradox of KD: despite the well-established pro-hypertrophic effect of androgen signaling and the fact that even polyQ-AR seems to correctly orchestrate male development — including the increased accumulation of muscle mass and strength during male adolescence, why does polyQ-AR instead cause muscle atrophy at older ages? Anastasia hopes to continue working on this critically important question to help the men afflicted with KD and their families in the future in her own lab as an independent investigator, building off the exceptional mentorship and support of Dr. La Spada and the KDA community. Originally from St. Petersburg, Russia, Anastasia has been happy to call SoCal home for over 16 years since starting her undergraduate studies at the University of San Diego. In her free time, she enjoys baking for the lab, supporting the San Diego Zoo Wildlife Alliance, and training to compete in powerlifting.
