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. The molecular mechanisms of neurite outgrowth inhibition in the central nervous system

We are determining the identity and mechanism of action of proteins that inhibit spontaneous regeneration in the central nervous system following injury. We are studying molecular processes that participate in outgrowth inhibition both at the level of the receptor-ligand interaction and the downstream intracellular regulators of neurite outgrowth.
Sub-projects include:

Matrix Metalloproteinases (MMPs) - We previously identified MMP-mediated shedding of the Nogo receptor, a critical transducer of inhibitory signals, as a mechanism to attenuate neurite outgrowth inhibition and promote neuronal regeneration. We are interested in defining roles for MMPs in modulating neurite outgrowth, adhesion, and responses to inhibitory ligands, with the goal of identifying novel targets for promoting neuronal regeneration.

Intracellular regulators of regeneration - We are particularly interested in the Rho family of small GTPases due to their effects on cytoskeletal dynamics and morphology. We are studying several proteins including RhoA and its effector ROCK, proteins that affect actin cytoskeleton regulators including ADF/cofilin and a cytosolic phosphoprotein, CRMP4. By elucidating how inhibitory ligands engage and signal through Rho GTPases and their effectors, we hope to identify convergent intracellular pathways that participate in neurite outgrowth inhibition


II. Growth cone dynamics and axon guidance

Axonal pathfinding during neuronal development and during regeneration is mediated by specialized tips at the leading edge of the axon called growth cones, which detect and integrate signals from multiple guidance cues. Growth cones respond to attractive and repulsive guidance cues by selectively stabilizing or destabilizing the cytoskeleton to achieve directional growth. 

Role of 14-3-3 proteins in axon guidance - We previously identified the 14-3-3 family of adaptor proteins as abundant constituents of the growth cone that play an important role in regulating growth cone turning responses, in part through regulation of protein kinase A. We are currently studying the role of 14-3-3s in additional aspects of commissural axon guidance. A particular emphasis in the lab is understanding the role of 14-3-3s in regulating the growth cone cytoskeleton. By studying the effects of 14-3-3s on the cytoskeleton, we hope to gain a better understanding of the mechanistic basis of 14-3-3-mediated regulation of growth cone dynamics.


III. Neural immune interface in Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disease characterized by the infiltration of pro-inflammatory immune cells into sites of active demyelination and axonal injury in the CNS. Axonal compromise is identified as the major contributor to permanent neurological disability in MS and in the experimental autoimmune encephalomyelitis (EAE) model. It is critical to elucidate mechanisms that may limit and/or promote axonal regeneration.

Impact of neuronal microRNA dysregulation on neurite outgrowth - By profiling microRNA expression in an in vitro MS paradigm and studying its effects on neurite growth, we hope to uncover how microRNA-mediated regulation of gene expression impacts neurite outgrowth and regeneration in an inflammatory context.