Research Areas

Objective

The primary aim of our research is to characterize the molecular basis of failed CNS regeneration in the adult as well as the basis for repulsive axon guidance during neural development.

Our current areas of focus are:

I. A polypharmacological approach to promoting axon regeneration

Numerous neurological conditions and traumatic injuries disrupt connections between neurons in the adult mammalian Central Nervous System (CNS). CNS neurons fail to spontaneously regenerate following injury and facilitating axon regeneration could support neurological recovery from a variety of conditions without having to introduce transplanted cells. There are currently no approved treatments to stimulate axon regeneration. A wealth of evidence has demonstrating that global alterations in the cell-intrinsic growth state of the neuron can promote axon regeneration following experimental nerve injury. However, these insights have failed to produce therapeutic strategies to promote repair. The recognition that a wide diversity of molecular mechanisms regulate axon regeneration has motivated us to pursue the idea that simultaneous engagement of multiple targets will offer a more robust approach to stimulate axon regeneration. We are thus pursuing a polypharmacological approache to regulate multiple pathways that promote axon regeneration using small molecules of the Fusicoccane family. Fusicoccanes modulate protein-protein interactions (PPIs) between the family of 14-3-3 cytosolic adaptor proteins, and an array of functionally diverse binding partners. We have discovered that fusicoccanes enhance axon regeneration. We have used a combination of proteomics, bioinformatics, small molecule screens and structural biology to characterize the mechanisms underlying this activity. We are pursuing the idea that fusicoccanes represent unique polypharmacological compounds to promote axon regeneration, that potent derivatives may be modified through medicinal chemistry to optimize their efficacy and that insights into their molecular mechanism of action can be probed to identify novel small molecules that may be harnessed to promote axon regeneration.


II. Neuroprotective Strategies for Multiple Sclerosis

In MS neuronal neuronal cell bodies and their processes are exposed to factors that impact neuronal viability and growth. Strategies that protect neurons and promote repair will be important elements in targeting neuronal pathology in MS. miRNAs are powerful regulators of gene expression that affect neuronal viability and growth. We explore the expression of neuronal miRNAs in response to pathological inflammation and study the functional roles of regulated miRNA in neuronal viability. These studies will aid in the conception and validation of therapeutic strategies to promote neuroprotection and repair in the context of MS.

III. Ectodomain shedding in neuronal development

During development, the nervous system must establish a series of high fidelity connections to mediate appropriate communication. It is estimated that every neuron in the human brain receives and makes around 10,000 synaptic contacts. Synapse assembly is a multi-step process of exploratory contacts between an axonal process and a post synaptic cell, contact stabilization and maturation of pre and postsynaptic molecular microdomains. Throughout life, synapses undergo structural modifications that correlate with memory and cognitive function, including changes in synapse density, morphology of dendritic spines and strength of synaptic signaling. Studying the fundamental biology of synapse formation is critical to understanding the normal function of the brain. It is also important because aberrant synapse formation has been linked to various neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Our studies seek to understand fundamental molecular mechanisms that regulate the formation and plasticity of synapses with a focus on how metalloproteinase-dependent shedding of molecules from the cell surface regulated synapse formation and dynamics.