A number of neuromuscular degenerative disorders are associated with the presence of these toxic RNAs. The goal of our laboratory is to understand how these expanded RNAs cause broad cellular dysfunction and disease. We aim to investigate the distinct mechanisms that regulate these pathogenic processes, with a particular emphasis on Myotonic Dystrophy.
Nucleotide sequence repeats are widespread in the human genome, with repetitive sequences present in non-coding as well as coding regions. Mutations resulting in expansions of these repeat sequences are associated with more than 40 disorders, mostly neuromuscular degenerative diseases.
RNAs bearing expanded repeats have emerged as the cause of complex pathogenic disorders, disrupting a wide range of essential molecular processes and whose mechanisms of RNA-mediated dysfunction are still poorly understood with many of the factors involved unknown. RNA repeat-based disorders include from Amyotrophic Lateral Sclerosis to Myotonic Dystrophies (DMs).
Our laboratory aims to uncover the pathogenic mechanisms that underlie RNA repeat mediated cellular dysfunction, in particular Myotonic Dystrophies (DMs).
Toxic RNAs, bearing expanded nucleotide repeats, disrupt a variety of cellular processes, which result in changes in signaling and metabolism. While the importance of these pathways is well established, we are interested in understanding, at a molecular level, how toxic RNAs disrupt metabolic pathways and the mechanisms by which different tissues may modulate RNA toxicity.
The developmentally-regulated RNA-binding factor Muscleblind-like (MBNL) family functions as a postnatal switch, which by reprograming splicing, modulating mRNA stability, sub-cellular localization and alternative polyadenylation drives developmental transitions and cell regeneration. MBNL has also been implicated as a modifier in different neuromuscular degenerative disorders, which include Myotonic Dystrophies (DM) and Spinocerebellar Ataxia 3 (SCA3). In DM, MBNL is sequestered resulting in changes in splicing of a number of genes and affecting a wide range of biological functions, yet for many of the transcripts affected the organismal implications of these dysregulations are not well understood.
Our laboratory takes a genetic approach to understand MBNL self-regulation, its developmental regulation of key metabolic pathways and its organismal effects.