Research Summary

The Fallon lab studies two major areas: 1) Developing a novel therapy for Duchenne Muscular Dystrophy (DMD). 2) Learning and memory, with a focus on Fragile X Syndrome and autism.

 

Muscular Dystrophy

We are developing a novel therapy for DMD. One of the most promising avenues for treating this disease is the upregulation of utrophin, an autosomal homolog of the gene (dystrophin) that is mutated in DMD. We have shown that the extracellular matrix protein biglycan can be systemically delivered to dystrophin negative mice where it upregulates utrophin, counters dystrophic pathology and improves muscle function. We are currently manufacturing biglycan in a form that can be used in humans and are determining its pharmacological and toxicological profile. Our goal is to test the efficacy biglycan for treating muscular dystrophy in patients affected by DMD. Our lab is also investigating the mechanism of biglycan action. Current projects include determining: 1) the signaling pathways by which biglycan upregulates utrophin; and 2) the role of biglycan in orchestrating the assembly of the utrophin/dystrophin protein complex.

 

 

 

 

 

 

 

 

 

Systemically delivered recombinant human biglycan (rhBGN) counters dystrophic pathology in mdx mice

   

Learning and Memory: Fragile X Syndrome

In the second area we study how experience shapes neural circuitry. This process is fundamental to learning, memory and forging effective communication between self and the outside world. Our focus is on Fragile X syndrome, which is both the most prevalent inherited mental retardation and the most common single gene cause of autism (or Autism Spectrum Disorders; ASD). Recent evidence indicates that the behavioral parallels between FXS and autism reflect shared cellular mechanisms: both conditions are disorders of synaptic plasticity. In both diseases it is likely that there is failure of appropriate sculpting of neural circuitry in response to environment/experience. We have discovered a novel structure, the Fragile X Granule (FXG) that is expressed presynaptically. Intriguingly, FXGs are circuit selective and developmentally regulated. The distribution and timing of these granules correlates remarkably well with circuits known to be affected in autism – such as prefrontal cortex, cerbellum and limbic system. Our working hypothesis is that FXGs are involved in presynaptic plasticity and axonal pruning. Current projects in the lab include the selective manipulation of presynaptic FMRP/FXGs using Cre-lox methodology in vivo and compartmentalized cultures where we can isolate axonal fractions. Our goals are: 1) To identify the RNA cargo of FXGs; 2) To determine the protein composition of FXGs; 3) To demonstrate the function of FXGs in synaptic plasticity.

 

 

 

Fragile X granules in the hippocampus