Lamitina Lab
at the University of Pittsburgh

The genes and signaling pathways that respond to many stressors, such as temperature and oxidative stress, are well defined.  In contrast, little is known regarding how cells respond to changes in water availability, or osmotic stress.  We are using unbiased forward genetics and whole-genome resequencing, genome-wide RNA interference, and in vivo imaging to identify the genes and pathways that permit C. elegans to respond to an osmotic challenge.  Our screens are revealing unanticipated new pathways that regulate this physiological response via both transcriptional and post-transcriptional mechanisms.  Interestingly, all of the genes identified in our screens are highly conserved from worms to humans. The study of these genes is not only providing insight into this essential stress response pathway but also illustrating new roles for many important cellular processes.

The expansion of G-C rich DNA sequences are the genetic cause of >40 distinct diseases, including neurodegenerative diseases like ALS/Lou Gehrig's disease, Huntington's disease, and others.  For many years, it was thought that these expansion repeats caused toxicity either through toxic repeat-containing RNA or the translation of these RNA molecules into repetitive, aggregating proteins, like the polyGlutamine (polyQ) protein associated with Huntington's disease.  Recent work has revolutionized our understanding of these diseases.  Remarkably, the repetitive sequences can prime a unique type of translation that is not dependent on a 'start AUG' codon and has no set reading frame.  This process is referred to as 'Repeat-associated non-AUG-dependent (RAN) translation.  We are building C. elegans models for each of these RAN translation products.  Combined with the unique experimental strengths  of C. elegans, we are using these new models to better understand how these previously unknown proteins might be associated with disease.