2013 Pilot Projects

Description

Our objective is to find new treatments for neuronal injury and disease by promoting regeneration of axons through the “preconditioning” response. Preconditioning is the phenomenon where a prior neuronal injury stimulates an improved regenerative response to a subsequent injury. Our long-term goal is to identify candidate drugs and/or genes that can activate the pro-regenerative preconditioned state without the need for a prior injury. To accomplish this goal, we will study the preconditioning response of human neurons derived from induced pluripotent stem cells (iPSCs). These stem cells are themselves derived from human skin and so are readily accessible and can be derived from patients with neurological disease. These patient-derived iPSCs will allow us to explore cellular models of neurological disease, such as ALS, in which enhanced regeneration would be helpful. If successful, these studies will allow us to perform large-scale screens for factors that promote regeneration of human neurons.

Publications

Frey, E., Valakh, V., Karney-Grobe, S., Shi, Y., Milbrandt, J., and DiAntonio, A.  An In Vitro Assay to Study Induction of the Regenerative State in Sensory Neurons. Experimental Neurology Volume 263, Pages 350-363, (2015).

Hao, Y., Frey, E., Yoon, C., Wong, H., Nesterovski, D., Holzman, L., Giger, R.J., DiAntonio, A., and Collins, C.  An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the DLK kinase. eLife 5:e14048. PMC4896747 (2016).

Frey E, Karney-Grobe S, Krolak T, Milbrandt J, DiAntonio A. TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca2+/PKA Signaling. eNeuro. 2018 May 30;5(3). pii: ENEURO.0095-18.2018.

Updated January 2019

Description

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is caused by the relentless death of motor neurons in both the brain and spinal cord.  Degeneration of these neurons results in progressive paralysis of muscles and eventually leads to death when the ability to breathe is lost, typically in less than 5 years after the onset of disease.  The loss of neurons in ALS is accompanied by the proliferation and activation of microglia, which are cells of the innate immune response.  It was once thought that microglia were simply responding to neuronal degeneration, but mounting evidence from human and mouse studies demonstrate that microglia are active participants in the disease process.  However, their role is nuanced, as microglia can adopt either neuroprotective or neurotoxic phenotypes and can transition between these two states. Biasing microglia toward neuroprotection and away from neurotoxicity could potentially treat ALS and other neurodegenerative diseases where microglia are implicated.  Recently, the TREM2 receptor pathway has been identified as a potential regulator of the microglial phenotype.  This project will determine whether genetic variability in, or expression of, TREM2 pathway genes are a risk factor for ALS or influence disease.  Additionally, TREM2 levels will be genetically manipulated in a mouse model of ALS to determine if TREM2 signaling influences the severity or course of disease.

Updated June 2017

Description

Brain injury is the main cause of disability in children. Following brain injury, children often compensate remarkably well. It is thought that the developing human brain compensates for injuries through use-driven reorganization of the remaining intact brain structures, but the mechanisms remain unknown. Understanding these mechanisms is important for designing neurorehabilitative treatments that enhance recovery. Constraint-induced movement therapy (CIMT) is a treatment for one-sided weakness that requires restraining the stronger upper extremity while undergoing intense therapy for the weaker side. CIMT provides an elegant model-system for studying the neural mechanisms of use-driven brain reorganization. Advances in magnetic resonance imaging (MRI) of the brain (“multi-modal brain MRI”) now allow us to track changes in the brain’s functional organization. To identify brain changes most important for improved motor behavior we also need to acquire accurate, unbiased data about real-world behavior. This project will pioneer the use of wearable movement biosensors in children to provide continuous measures of three-dimensional extremity movement, from which we can derive the accurate outcome measures needed for clinically useful brain-behavior correlations. Merging advanced multi-modal MRI and biosensor technologies will identify functional links between brain regions most important for improving real-world movement in children. Such critical brain links can then be targeted with medications, therapies, brain stimulation and neurofeedback.

Grants and Awards

“Evaluating therapeutic brain reorganization in children with spastic paralysis using functional MRI and wearable biosensors”
Spastic Paralysis Research Foundation Kiwanis International, Illinois-Eastern Iowa District
This award provides funds to study real-life motor activity in children with hemiplegia and typically developing controls using wearable accelerometry biosensors.

Early Career Research Fellowship (Dosenbach)
Jacobs Foundation
This fellowship provides funds for studying neurorehabilitation in children with brain injury.

“Pediatric brain injury recovery via use-driven functional network reorganization” 
NINDS K23 NS088590 (PI, Dosenbach)
Keys to unlocking the brain’s remarkable capacity for recovery after injury can be found in its complex network architecture. Therefore, we aim to understand how constraint-induced therapy drives network reorganization.

Updated June 2017