Pilot Project awards in 2022 and 2021
Hope Center Pilot Awards provide funding for two-year projects. Teams include Hope Center faculty members and others. Click ‘project details’ below to learn more.
Effect of Air Pollution on Abeta and Tau Metabolism in Mice
Principal Investigator: John Cirrito (WashU Neurology)
Collaborators: Rajan Chakrabarty (WashU Energy, Environmental & Chemical Engineering)
Growing evidence suggests that prolonged exposure to air pollution increases the incidence of brain-related diseases, including increasing the risk of developing Alzheimer’s disease. We will expose mice to particulate matter observed in urban environments to mimic a range of exposure conditions worldwide, including emissions from diesel fuels, biomass burning, metal-rich soot, and inorganics. Dr. Chakrabarty’s laboratory in the School of Engineering specializes in producing and analyzing these types of pollutants. While mice are inhaling these agents, the Cirrito laboratory will perform in vivo microdialysis to measure brain interstitial fluid Aβ levels hourly to determine how levels and clearance rates change in real-time during intermittent exposure. We had a custom inhalation chamber built to expose mice while performing these studies in a safe manner. The findings from this study will provide preliminary data whether air pollution has a direct and causal impact on Alzheimer’s-related processes.
Alzheimer’s disease pathology in patients with multiple sclerosis
In large part due to the emergence of highly effective disease modifying therapies, patients with multiple sclerosis are living longer with less disability related to their multiple sclerosis. An unfortunate consequence of this generally positive development is that patients with multiple sclerosis are increasingly at risk for age-related conditions. The largest risk factor for development of Alzheimer disease is advancing age. Thus, it would be predicted that an increasing aging population of multiple sclerosis patients would lead to an increase in co-morbid multiple sclerosis and Alzheimer disease. However, in our clinical experience the co-occurrence of these two diseases is more uncommon than would be expected. This leads to two competing possibilities: 1) multiple sclerosis patients do not develop Alzheimer disease or 2) patients with both multiple sclerosis and Alzheimer disease present in a way such that their dementia goes unrecognized. This study leverages increasingly accessible blood-based biomarkers of Alzheimer pathology to determine if the Alzheimer disease is pathologically present in older patients with multiple sclerosis. If we find that Alzheimer disease pathology is less common in multiple sclerosis patients that would suggest that either multiple sclerosis or its treatment is protective against Alzheimer disease. Conversely, the opposite result would motivate work to identify patients with comorbid disease which is especially urgent given increasing hope for an efficacious therapy for Alzheimer disease.
High-throughput Pathogenicity Prediction of FKTN Gene Variants causing Congenital Muscular Dystrophy with Brain and Eye anomalies
Mutations in Fukutin (FKTN) cause congenital muscular dystrophy with eye and brain anomalies (CMDBEA), a form of alpha-dystroglycanopathy with devastating effects for patients. Accurately diagnosing patients genetically, prenatally or early in the course of the disease, has the potential to enable the use of preventative gene therapy or other therapeutics. Our goal is to empirically determine the effect of many different mutations in the FKTN gene, enabling accurate prediction from genetic information before birth to identify who is most likely to develop this condition and potentially prevent it before it begins. We propose a new approach to characterize the function of numerous missense variants in FKTN using a set of high-throughput cellular assays of FKTN function to test the accuracy of our predictions using in-depth clinical information from patients. We hope this work will advance our understanding of muscle biology, improve the interpretation of genetic variation in FKTN, and advance CMDBEA care and treatment.
Harnessing pro-regenerative immune responses to promote spinal cord repair
Spinal cord injuries are devastating, incurable conditions that require long-term therapeutic, rehabilitative and psychological interventions. Thus, developing therapies to treat or reverse spinal cord injury is a pressing need in regenerative medicine. In contrast to humans, teleost fish naturally regenerate functional neural tissue and reverse paralysis within 6-8 weeks of complete spinal cord injury. While accumulation of cellular debris and defective clearance mechanisms are hallmarks of human spinal cord lesions, adult zebrafish possess pro-regenerative immune cells that direct efficient debris clearance and support their natural recovery. This proposal will dissect the pro-regenerative role of the immune system in zebrafish and will devise zebrafish-inspired approaches for manipulating human immune cells to promote debris clearance and spinal cord repair in humans.
Role of KATP channels in neurovascular coupling and disease
The neurodegeneration that occurs in Alzheimer’s disease may be linked to changes in brain blood flow and its control. We have shown that drugs which target KATP channels, proteins in the membranes of cells that line blood vessels, can alter the progression of Alzheimer’s disease in animals. We plan to work out where exactly these drugs are acting. This will help us fully define the role of KATP channels in brain blood flow control, and determine the potential for targeting KATP channel modulation as a therapy for Alzheimer’s disease.
Patient-Specific Neuroimaging Markers of Recovery After Traumatic Brain Injury
Recovery from Traumatic Brain Injuries (TBIs) can be slow and difficult to predict, and the neural processes underlying such recovery are not well understood. In this proposal, we will use noninvasive neuroimaging techniques to precisely track changes in brain structure and function that happen during recovery from TBI. This tracking will be done separately within individual acute TBI patients, which will help us understand how individuals’ recoveries may vary from each other. Tracking will continue for up to six months in order to characterize the entire recovery timeframe. The knowledge gained from this work will help us understand how and why TBI symptoms resolve when they do, and why recovery can vary so much across individuals. It may thus allow more accurate prognoses of TBI recovery. It will also be critical for developing future personalized, neurologically-based treatments that target dysfunctional brain structures within individual patients.
A model of human neuroprotection
Principal Investigator: Daniel Kerschensteiner (WashU Ophthalmology & Visual Sciences)
Collaborator: Philip Ruzycki (WashU Ophthalmology & Visual Sciences)
Photoreceptors translate light into neural signals that form the basis of vision. A diverse group of inherited retinal degenerations (IRDs) causes photoreceptor loss and visual impairment, including blindness, in approximately 1:2000 people. The genetic heterogeneity of IRDs makes the development of mutation-specific therapies, with few exceptions, impractical. Here, we will perform a genome-wide search for mutation-agnostic neuroprotective strategies that could benefit many IRD patients. To speed up the translation from animal models to humans, we developed a sequential search strategy combining in vivo experiments in mice and large-scale candidate testing in human retinas.
Brain injury creates a supportive microenvironment for tumorigenesis
In addition to cancer cells, brain tumors form in an environment with non-cancerous cells (immune and nerve cells) that are critical for tumor formation. Brain injury may create changes in the brain microenvironment similar to those found in brain tumors, raising the intriguing possibility that brain injury creates a supportive environment for brain tumor formation. Using a mouse model of the Neurofibromatosis type 1 (NF1) brain cancer predisposition syndrome, we propose to determine whether injury can facilitate tumorigenesis. Insights from these studies may provide potential therapeutic opportunities to block tumor growth in children and adults with NF1 unrelated to brain injury, as well as in other tumor predisposition syndromes.
Mapping ketamine-orchestrated translatome to rapid-acting anti-anhedonic effects at the synaptic level with cell-type specific resolution
Principal Investigator: Marco Pignatelli (WashU Psychiatry)
Collaborator: Vijay Samineni (WashU Anesthesiology)
Anhedonia—defined as diminished pleasure from, or interest in, previously rewarding activities—is a widely reported symptom of many psychiatric and neurological illnesses. A promising and novel treatment for anhedonia is represented by ketamine. Indeed, recent clinical evidence has shown that a single injection of ketamine ameliorates anhedonic symptoms within a matter of hours. However, understanding of the neurobiological mechanisms underpinning ketamine’s anti-anhedonic effects is lacking. Accordingly, the goal of this proposal is to develop a circuit and synaptic framework for ketamine’s mechanism of action in alleviating anhedonia. Specifically, using chronic stressed mice as a model system, we are planning to identify specific cellular and synaptic elements recruited by in vivo K administration and responsible for its anti-anhedonic effects within the Nucleus Accumbens, a brain region critical for mood and hedonic drive. No therapeutics are currently approved for the treatment of anhedonia despite its prevalence across multiple psychiatric and neurological disorders, therefore identifying mechanisms mediating ketamine’s ability to ameliorate hedonic deficits may provide cardinal stepping stones toward treatment improvements for this tractable endophenotype.
VEGFA as a potential therapeutic target to enhance motor recovery following acute and chronic nerve injury
Principal Investigator: Alison Snyder-Warwick (WashU Surgery)
Collaborators: Jianjun Guan ( WashU Mechanical Engineering & Materials Science)
Injuries to the Peripheral Nervous System are burdensome on individuals and society as a whole. Despite advances in neuroscience and reconstructive nerve surgery, recovery after peripheral nerve injuries often remains incomplete. Functional outcome worsens with increased time for nerves to reconnect with muscles. Compared to nerves, less investigative focus has centered on the muscle and the neuromuscular junction (NMJ), which is the interface between nerve signals and muscle movements. Terminal Schwann cells (tSCs) help with NMJ function, and following nerve injury, these tSCs guide nerve fibers back to the NMJs. We have identified Vascular Endothelial-derived Growth Factor A (VEGFA) as a key growth factor required for NMJ recovery after nerve injury with immediate nerve repair. Specifically, we have found that blocking VEGFA signaling results in a reduction of tSCs guidance of nerve fibers to the NMJs and overall fewer nerve fibers reaching NMJs. Additionally, we showed an increase in VEGFA receptors on tSCs after injury. Clearly, VEGF signaling loss after early nerve repair results in worse muscle function. What happens to VEGFA and the NMJ after delayed repair is not known, nor is the possible benefit of VEGFA enhancement to muscle after nerve injury in either the acute or chronic settings. This project investigates whether exogenous VegfA delivery to the end target muscle following nerve injury and immediate or delayed repair can enhance functional recovery. If successful, additional studies will be planned to translate this finding clinically for localized delivery at the affected muscle. With this knowledge, treatment of the high number of nerve injuries can be improved.