Research Summary

Dr. Castoro has a primary focus in peripheral neuron degeneration.  Our primary focus is developing imaged based biomarkers for measuring peripheral neuron axonal loss in peripheral nerve diseases.  Measuring axonal loss is critically important to upcoming clinical trials in peripheral nerve diseases.  However, to date we have no methods which can directly measure axonal loss (or gain) in humans which limits our ability to develop and translate treatments for these individuals.   Our preferred imaging modality is Ultrasonography because it is accessible across the world, is a bedside, non-radiation emitting technique that allows for extremely high resolution far superior to other techniques like MRI.  Unfortunately, because of image processing required for clinical ultrasound machines, they are unable to quantify subtle changes in peripheral nerves because of their relatively small size in comparison to other structures.   To overcome this, we use a technique known as quantitative ultrasound which allows us to develop image processing method which can be used to measure the subtle, but critical changes in peripheral nerves that correlate with neuron axonal loss. We use rodent models to correlate our ultrasound techniques with  with axonal loss, myelin loss and collagen deposition.  Using this method, we aim to translate our findings into humans to demonstrated ultrasound as a viable method to detect axonal loss.  

We also study the process of peripheral neuron degeneration at the molecular level.  Specifically, we are interested in how DNA methylation affects peripheral motor neuron degeneration.   DNA methylation is one of many EPI-genetic modifications that regulate mammalian gene expression.  Epigenetic modifications such as DNA are both inherited and acquired often times leading to aberrant over- or decreased- expression of critical genes required for cellular homeostasis.  DNA methylation in particular, when found aberrantly in CpG islands of promoter regions can cause hetero- or eu-chromatic changes in the genome that effect gene expression. Thus, it's conceivable that diseases such sporadic amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) are caused by aberrant DNA de- or hyper-methylation.  In the same line Mendiallian inherited diseases such Charcot-Marie-Tooth, a sensory and motor peripheral nerve disease caused by mutations in a single gene, likely undergo secondary epigenetic related changes due to the gain- or loss- of function of the mutant gene. Understanding these secondary epigenetic (or primary in the case of motor neuron diseases) changes will be critical in order to provide more effective treatments to these individuals.  Our studies utilize direct conversion of human fibroblasts into motor neurons and murine models to study the effects of DNA methylation in motor neurons with the aim to develop biomarkers and treatments for peripheral nerve and motor neuron diseases.