Faculty

Janice A. Dominov, Ph.D.
Assistant Professor of Neurology

Research Areas

Muscular dystrophies, amyotrophic lateral sclerosis (ALS), cellular and molecular mechanisms underlying disease pathogenesis and therapeutic strategies for treatment

Biography

Janice Dominov is an Assistant Professor in the Neurology Department at UMass Chan Medical School.  She earned a B.S in Microbiology at the University of Rhode Island then focused her early research on molecular mechanisms that regulate cell fate and developmental processes. She earned a Ph.D. in Biology at Case Western Reserve University in the laboratory of Christopher Town studying regulation of cell type specification in Dictyostelium discoideum, a model organism broadly used for studies of cell signaling and cellular differentiation. She extended these interests in the regulation of developmental processes a postdoctoral fellow at the University of California San Diego in the laboratory of Stephen Howell, focusing on hormonal regulation of plant cell type differentiation in the model organism Nicotiana plumbaginifolia. Her interests in developmental programs then turned to mammalian systems, specifically, molecular pathways that play a role in embryonic and postnatal and skeletal muscle development and regeneration. As a postdoctoral fellow, and then Instructor in the laboratory of Jeffrey Miller at Massachusetts General Hospital and Harvard Medical School, she identified proteins transiently expressed during mouse fetal myogenesis, studied effects of a myogenic regulatory factor on the temporal progression of myogenesis, and identified the apoptotic regulatory protein BCL-2 as a marker of muscle stem cells in postnatal mouse muscles.  

Dr. Dominov joined the Boston Biomedical Research Institute (BBRI) as an Instructor, where she studied pathogenic mechanisms and the role of apoptosis regulation in muscle degeneration in mouse models of Duchenne (dystrophin-deficient) and congenital laminin a2-deficient (Lama2) muscular dystrophies. She established her independent laboratory as a Scientist at BBRI, turning her focus to early events in congenital muscular dystrophy pathogenesis where she identified innate immune system activation and expression of Toll-like receptors (TLRs) as a key early feature of disease that likely plays a role in disease progression. Dr. Dominov then moved her lab to the University of Massachusetts Medical School, joining the Neurology Department as an Assistant Professor, where she has continued her work on skeletal muscle diseases.

Current Research

Dr. Dominov has recently pursued research interests in the pathogenesis and genetics of adult-onset forms of muscular dystrophy, specifically those caused by dysferlin-deficiency (dysferlinopathies: Miyoshi myopathy, limb girdle muscular dystrophy type 2B, LGMD R2). She used an RNA sequencing approach on patient cell lines to identify two novel pathogenic deep intronic dysferlin mutations that cause aberrant dysferlin RNA splicing and loss of normal protein expression. She then developed antisense oligonucleotides that can correct the mis-splicing cause by each of these mutations, restoring normal RNA transcripts and increasing dysferlin protein levels. Several novel dysferlin mutant mouse models have been created in the lab, including one for a mis-splicing mutant and others that emulate additional dysferlinopathy patient mutations. Current efforts are focused on studies in these new pre-clinical animal models to test therapeutic strategies and move them toward clinical application.

Along with her long-term interests in skeletal muscle development, regeneration, disease pathogenesis and therapeutics, Dr. Dominov has research projects, in collaboration with Dr. Robert Brown, studying motor neuron disease and ALS pathogenesis. New knock-in mouse models for several human superoxide dismutase 1 (SOD1) mutations that cause ALS have been created as tools to study disease. Gene expression and other analyses of motor neurons in these mice have identified physiological changes associated with disease that might offer new insight into motor neuron death mechanisms and new strategies for therapeutic intervention.

Select Publications

1. Dominov JA, Uyan O, McKenna-Yasek D, Nallamilli BRR, Kergourlay V, Bartoli M, et al. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. Ann Clin Transl Neurol. 2019;6(4):642-54.
2. Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, et al. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018;97(6):1268-83 e6.
3. Dominov JA, Uyan Ö, Sapp PC, McKenna-Yasek D, Nallamilli BRR, Hegde M, et al. A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides. Annals of Clinical and Translational Neurology. 2014;1(9):703-20.
4. Jeudy S, Wardrop KE, Alessi A, and Dominov JA. Bcl-2 Inhibits the Innate Immune Response During Early Pathogenesis of Murine Congenital Muscular Dystrophy. PLoS ONE. 2011;6(8):e22369.
5. Wardrop KE, and Dominov JA. Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin {alpha}2-Deficient Skeletal Muscle. J Histochem Cytochem. 2011;59(2):167-79.
6. Dominov JA, Kravetz AJ, Ardelt M, Kostek CA, Beermann ML, and Miller JB. Muscle-specific BCL2 expression ameliorates muscle disease in laminin {alpha}2-deficient, but not in dystrophin-deficient, mice. Hum Mol Genet. 2005;14(8):1029-40.
7. Girgenrath M, Dominov JA, Kostek CA, and Boone Miller J. Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy. J Clin Invest. 2004;114(11):1635-9.