Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty click on their names below. Descriptions and progress of each award can be found in the project details.
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.