2016 Pilot Projects

Description

Sleep disturbances cause decrements in quality of life, contribute to mental health disorders, and may play a critical role in multiple neurodegenerative diseases. This study aims to define the neurocircuitry involved in circadian regulation of sleep and identify novel key points in this circuitry that can be manipulated to improve sleep function. One key neuropeptide that will be examined in this proposal, dynorphin, has multiple compounds and small molecules in various stages of development. The proposed studies will offer fundamental new insights into the regulation of sleep and will offer novel targets for future development in the treatment f sleep and related disorders.

Grants and Awards

A Novel Node in Threat Response Neurocircuitry: VGLUT2 Positive Supramammillary Neurons Projecting to Preoptic Hypothalamus
NIH/NIMH 5K08MH119538 (PI, Norris)
Public Health Relevance Statement: Areas of the brain that respond to threat and other stressors are important in neuropsychiatric diseases. This study aims to delineate the roles of a poorly studied brain region, the supramammillary nucleus, that recent findings indicate is critical for regulating responses to stressors. The role of this region of the brain in responding to stressors is uncharacterized and it may play an important role in mediating active coping responses.

Light-Induced Targeted Recombination Strategies For Genetic Access to Recently Active Neurons
NIH/National Eye Institute 1R21EY031269 (PI, Norris)
Public Health Relevance Statement: PROJECT NARRATIVE The goal of this work is to develop new tools to allow genetic access to recently active neurons. These tools will enable visualization and manipulation of neural circuit activity selectively in neurons that have recently fired, allowing researchers to modulate specific neural circuits in the brain with high temporal precision. These tools will lead to better understanding of the neural circuitry giving rise to perception, memory, complex thought, and behavior, and how these are altered by disease states and neurological disorders.

Publications

Aaron J Norris, Jordan R Shaker, Aaron L Cone, Imeh B Ndiokho, Michael R Bruchas. Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses. eLife 2021;10:e60779

Updated April 2021

Description

Autosomal dominantly inherited mutations in the gene DES, which encodes the desmin protein, lead to devastating protein aggregate myopathies with premature death. Our proposal adopts a novel pathomechanistic paradigm that has not been investigated in skeletal muscle diseases associated with protein accumulation. Specifically, we will investigate the role of templated protein conversion in skeletal muscle. In addition, we will explore whether prion like protein transmission can occur from myofiber to myofiber. Finally, one mechanism for the phenotypic pleiotropy may relate to distinct protein aggregate conformations similar to those seen in neurodegenerative disorders. These studies will enable novel therapeutic interventions and diagnostic testing that has not been considered in these rare degenerative myopathies.

Publications

Niraja Kedia, Khalid Arhzaouy, Sara K. Pittman, Yuanzi Sun, Mark Batchelor, Conrad C. Weihl, and Jan Bieschke. Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers. PNAS 2019 Aug 20;116(34):16835-16840.

Updated August 2019

Description

Damage to a peripheral nerve often results in a defect between the proximal and distal nerve stumps that cannot be directly repaired without excessive tension limiting regeneration. While a nerve autograft remains the “standard of care” for these defects, it has disadvantages for the patient. However, adequate functional recovery after a nerve injury reconstructed with a long nerve autograft alternative (nerve construct) is rarely achieved. This outcome is due to few axons regenerating across the construct. This project utilizes bioengineering techniques to tailor the material properties of nerve to develop clinically-relevant constructs to improve nerve regeneration. In addition, this approach develops multiple variants of nerve constructs with tuned material properties yielding a library of constructs. This library will provide the ability to assess how material properties (mechanical and biological cues) impact nerve cell populations and signaling pathways during nerve regeneration.

Grants and Awards

“T cell roles in regeneration across nerve graft alternatives”
NIH/NINDS R01NS115960-01 (PI Matthew Wood)
Public Health Relevance Statement: PROJECT NARRATIVE Approximately 2-3% of trauma cases involve peripheral nerve damage. The treatment options for these injuries are limited, and clinical outcomes following surgical reconstructions can yield incomplete recovery, where estimates of adequate recovery are only achieved in 52% of cases. This project advances scientific knowledge on principles of nerve regeneration and functional recovery, where there is significant potential that the outcome of the research could lead to new therapies to improve the treatment of nerve injuries.

Publications

Pan D, Hunter DA, Schellhardt L, Jo S, Santosa KB, Larson EL, Fuchs AG, Snyder-Warwick AK, Mackinnon SE, Wood MD. The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration. Exp Neurol. (2019) Aug; 318:216-231.

Pan D1, Mackinnon SE1, Wood MD1. Advances in the repair of segmental nerve injuries and trends in reconstruction. Muscle Nerve. (2019) Dec 27

Updated April 2021