2017 Pilot Projects

Description

Damage to a peripheral nerve encountered following amputation or trauma often results in the formation of neuroma, which is a bundle of nerve and scar tissue that can cause debilitating pain. Strategies are needed to prevent and/or treat this pain-inducing state. This proposal is based on our preliminary studies showing that neuroma can be treated with a surgical intervention that involves excision of the neuroma and attaching an acellular nerve allograft (ANA) cap. This procedure allows axons to grow into the ANA, but not exit the long graft as the support for regeneration is diminished. We hypothesize that this surgical intervention allows neurons to turn off their growth program, which is essential to prevent chronic pain states. We will elucidate the molecular mechanism underlying the beneficial effects of using ANAs in neuroma prevention. This research will support the clinical implementation of using ANAs in neuroma treatment.

Updated April 2021

Description

Alzheimer’s disease is initiated by the accumulation of amyloid-beta aggregates around neurons in the aging brain. A key factor that drives aggregation of amyloid-beta is high concentrations of the peptide. Normally, amyloid-beta is at low levels because it is readily cleared from the brain by several mechanisms including its drainage system (the glymphatic system). This system needs a special water channel (Aqp4) to control fluid flow. We recently found a new form of Aqp4 can be generated in the brain by a process called stop codon readthrough. With Hope Center support, we aim to test whether this new form of Aqp4 can be used to drive better clearance of amyloid-beta in Alzheimer’s test models in order to keep levels low and reduce toxic accumulation. We also aim to identify genes and drugs that can make more of this Aqp4 form in the brain.

Grants and Awards

Neurobiological significance of Aqp4 stop codon readthrough
NIH/NIA 5K99AG061231 (PI, Darshan Sapkota)
Public Health Relevance Statement: Project Narrative The concentration of amyloid-β (Aβ) is directly linked to its likelihood to aggregate into toxic species in the Alzheimer’s disease brain. This proposal will determine the role of Aquaporin-4 (Aqp4), particularly an elongated readthrough version of the protein that occurs naturally, in regulating Aβ clearance via astrocytes. Elucidating the mechanisms that regulate Aβ concentration will provide insight into disease pathogenesis as well as risk of disease, and could suggest a new therapeutic target to enhance Aβ clearance from the brain.

Publications

Darshan Sapkota, Allison M. Lake, Wei Yang, Chengran Yang, Hendrik Wesseling, Amanda Guise, Ceren Uncu, Jasbir S. Dalal, Andrew W. Kraft, Jin-Moo Lee, Mark S. Sands, Judith A. Steen, Joseph D. Dougherty. “Cell-Type-Specific Profiling of Alternative Translation Identifies Regulated Protein Isoform Variation in the Mouse Brain”. Cell Reports, Volume 26, Issue 3, 15 January 2019, Pages 594-607.e7

Darshan Sapkota, Colin Florian, Brookelyn M Doherty, Kelli M White, Kate M Reardon, Xia Ge, Joel R Garbow, Carla M Yuede, John R Cirrito, Joseph D Dougherty. “Aqp4 stop codon readthrough facilitates amyloid-β clearance from the brain”. Brain, Volume 145, Issue 9, September 2022, Pages 2982–2990,

Updated April 2023

Description

Conventional upper-limb prostheses are limited by their inability to provide sensory feedback (i.e., a sense of touch), rendering prosthetic control unintuitive and cumbersome. Developing technologies to overcome this barrier remains an area of active research today. Our research group focuses on one such technology: the macrosieve electrode (MSE). When implanted in residual peripheral nerve following amputation, the MSE can direct electrical currents through the nerve tissue to generate sensations that appear to originate in the phantom limb. This project examines two aspects of MSE performance that will determine its clinical viability. First, it seeks to establish the minimum current threshold required to trigger a sensation; lower thresholds are preferable for reasons related to biocompatibility and power. Second, it examines whether currents directed through different parts of the nerve produce sensations localized to different parts of the phantom limb. If yes, then the MSE’s versatility as a sensory interface will be greatly augmented.

Publications

Nikhil S. Chandra, Weston M. McCarron, Ying Yan, Luis C. Ruiz, Eric G. Sallinger, Nathan K. Birenbaum, Harold Burton, Leonard Green, Daniel W. Moran, Wilson Z. Ray, and Matthew R. MacEwan. Sensory Percepts Elicited by Chronic Macro-Sieve Electrode Stimulation of the Rat Sciatic Nerve. Frontiers in Neuroscience. 2021; 15: 758427.

Updated November 2021

Description

Lysosomes are structures inside all cells that are mainly responsible for clearing and recycling damaged or worn out components of the cell. The lysosomes contain enzymes that degrade cellular waste into its constituent components which the cell can recycle or discard. Childhood neurodegenerative diseases can result from severe lysosome failure which subsequently causes cellular waste to accumulate. In recent years, it has been shown that mild lysosome dysfunction predisposes a person to develop Parkinson’s disease. The goals of this project are to determine if lysosome dysfunction caused by genetic defects in lysosome enzymes 1) affects α-Syn uptake, trafficking, aggregation and clearance in cultured primary neurons and 2) affects α-Syn spreading in intact animal models.

Updated April 2021