Active Pilot Projects

Description

The aggregation and dysfunction of TDP-43 characterizes multiple neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. This pathology also affects individuals with a common neurodegenerative dementia, recently named limbic-predominant age-related TDP-43 encephalopathy (LATE), that afflicts greater than a quarter of individuals over 80 years of age. In addition, TDP-43 aggregates are present in Alzheimer’s disease and patients with traumatic brain injury. TDP-43 is an essential RNA binding protein that regulates gene expression. The accumulation of TDP-43 aggregates in neurons is accompanied by loss of normal protein localization, and affected patients show dysregulation of genes controlled by TDP-43. Hence, TDP-43-linked pathogenesis likely stems from the combined effect of aggregate toxicity and impaired protein function. Finding strategies to decrease aggregate burden and restore normal TDP-43 activity is an urgent priority. However, TDP-43-targeted therapies are currently underdeveloped. Our project focuses on generating compounds to prevent neurotoxicity by degrading TDP-43 aggregates specifically without affecting the functional protein. To develop these specific degraders, we will harness small molecules that we previously found to bind TDP-43 aggregates only. We will determine the efficiency of these compounds in assays established in our labs to then test their unique properties in disease-relevant and in vivo models of TDP-43 proteinopathies.

Description

Amyotrophic Lateral Sclerosis (ALS) is a very complex and heterogenous disease. We have recently discovered abnormal frequencies of cytotoxic T lymphocytes in the spinal cord and peripheral blood of a juvenile form of ALS, called ALS-4, suggesting an interplay between the immune and central nervous system in disease progression. Here we are investigating whether ALS-4 associated T cells are directed against the nervous system.

By characterizing the nature of these T cell responses in ALS-4 and in the long term, in different forms of ALS, our goal is to unravel and refine disease mechanisms, identify subtype-specific markers, and design “personalized” treatments for specific populations of patients.

Description

Photoreceptors are specialized light-sensitive cells of the eye that allow us to see. Broadly speaking, there are two types of photoreceptors: rods and cones. Rods—the more numerous type of photoreceptor—enable vision in dim light, while cones enable vision in bright light. Degeneration of photoreceptors affects millions of people worldwide, leading to visual impairment and blindness. Because degeneration can be caused by many different factors, general purpose therapeutic interventions are sorely needed. This project is centered on the recent discovery that genetically rewiring rods to express cone genes confers protection against a range of different modes of degeneration. Using mouse models, we will determine how a rod-specific protein called SAMD7 represses cone genes in rods, with the goal of reversing this repression to enable protection from photoreceptor degeneration. If successful, these studies will define a novel approach for preventing photoreceptor degeneration which may eventually be applied to human patients suffering from blinding disorders.

Description

Sleep is fundamentally important for health and disease but much about sleep remains to be discovered. Understanding and manipulating sleep, particularly the dynamics of NREM sleep slow waves, can offer profound insights into the neurobiological mechanisms of sleep, its restorative functions, and its impact on cognitive and emotional well-being. The research project by Dr. Eric Landsness and Dr. Aaron Norris aims to develop a novel closed-loop brain-computer interface system for the dynamic modulation of sleep and wakefulness, with a focus on the manipulation of non-rapid eye movement (NREM) sleep slow waves.

This project seeks to enable precise, real-time control over sleep states and slow-wave activity, leveraging advances in optogenetics, EEG analysis, machine learning, and brain-computer interface technologies. By facilitating temporally precise, titratable alterations in sleep architecture, the research aims to deepen our understanding of the neurobiology of sleep, its impact on neurological and psychiatric diseases, and the fundamental mechanisms underlying slow waves. The project will target brain areas that are important for sleep, but whose detailed roles remain unknown.  The collaborative effort between the labs combines expertise in optogenetics, mouse surgery, EEG sleep analysis, and brain-computer interface development, aiming to innovate sleep science and provide new tools for the investigation of sleep’s roles in health and disease.

Description

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.

Updated March 2024

Description

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.

Updated February 2024

Description

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.

Grants and Awards

Massively-parallel functional interrogation of genetic variation in CMD-associated alpha-dystroglycan glycosylating enzymes
NIH/NIAMSD – 1R01AR081901-01A1 (PI, Haller)
Public Health Relevance Statement: The goal of this project is to use cell-based high-throughput assays to reliably predict the consequences of genetic variants of unknown significance discovered in the course of genetic testing in a subset of muscular dystrophies caused by mutations in a set of alpha-dystroglycan glycosylating enzymes: FKTN, FKRP, POMT1, POMT2, and POMGNT1. We propose to use an integrated experimental and computational approach that combines multiple high-throughput assays of protein trafficking and function and machine-learning to generate pathogenicity predictions for all possible single-nucleotide variants in these dystroglycanopathy genes and then validate and disseminate our predictions with respect to disease risk and severity using extensive clinical data and primary tissue samples from patients with muscular dystrophy.

Updated February 2024

Description

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.

Updated March 2024