Pilot Project awards in 2023

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.

2024 Awards

Unlocking the Power of Endothelin Signaling in Peripheral Neurogenesis

Principal Investigator: Valeria Cavalli (WashU Neuroscience)

Collaborator: Mayssa Mokalled (WashU Developmental Biology)

Project Details

Description

Sensory neurons, located in clusters called dorsal root ganglia (DRG), are essential for detecting and transmitting sensory signals like touch, pain, and body position to the brain. As we age or experience injuries, sensory perception can decline, affecting quality of life and even contributing to cognitive decline. While therapies to restore sensory function are urgently needed, current options remain limited. Interestingly, recent studies suggest that a type of supportive glial cell in the DRG, called satellite glial cells (SGCs), may act as a reservoir of stem cells capable of replacing lost sensory neurons. These SGCs retain the ability to self-renew and can even give rise to new sensory neurons after injury, but the signals that regulate this potential remain unclear.

Our research focuses on a signaling pathway involving endothelin, a molecule known to stimulate glial progenitor cell proliferation in the nervous system. Our proposal will unravel the role of endothelin signaling in SGCs self-renewal capacity and potential to generate new neurons. By studying how endothelin signaling regulates SGCs stemness behavior in mouse and zebrafish models, we hope to unlock their potential for cellular repair. This research could lead to innovative therapies for sensory disorders, including nerve injuries, peripheral neuropathies, and age-related sensory decline, improving health and quality of life for millions of people.


Sleep regulation of the brain-gut axis throughout lifespan

Principal Investigator: Yao Chen (WashU Neuroscience)

Collaborator: Meng Wu (WashU Molecular Microbiology)

Project Details

Description

Sleep is crucial for maintaining a healthy brain and healthy gut, but what mediates these effects? The gut microbiome—the community of tiny microbes living in our intestines—could hold the key. These microbes regulate digestion, brain function, and even mood. However, sleep loss can throw them out of balance, potentially leading to neurological and gut disorders. Our project aims to study how sleep disruption affects the microbiome, the brain, and the brain-gut axis at two critical life stages: adolescence and old age. By unlocking these mysteries, we hope to pave the way for new strategies to protect brain and gut health throughoutthe lifespan.


Functional network alterations in chronic pain as neuromodulation targets

Principal Investigator: Nico Dosenbach (WashU Neurology)

Collaborators: Benjamin Kay (WashU Neurology), Simon Haroutounian (WashU Anesthesiology), Hadas Nahman-Averbuch (WashU Anesthesiology)

Project Details

Description


Investigating brain glucose use in Alzheimer disease in vivo with multi-scale metabolic microscopy

Principal Investigator: Song Hu (WashU Biomedical Engineering)

Collaborator: Manu Goyal (WashU Radiology)

Project Details

Description

This project aims to advance our understanding of the changes in brain metabolism that occur in Alzheimer disease (AD), specifically how brain glucose use evolves as the disease progresses. Early in AD, the brain increases its glucose use, while later stages see a significant decline. Understanding this shift is key to identifying more effective treatments for slowing AD progression. To this end, the team plans to develop a cutting-edge imaging technique that will allow them to observe how glucose use, oxygen metabolism, and mitochondrial activity co-evolve in mouse models of AD. This new approach will provide valuable insights into how these metabolic changes contribute to AD and could lead to more targeted treatments. Ultimately, the researchers hope to expand their findings into larger studies that could inform future clinical therapies for AD.


Identification and validation of drug candidates for repurposing in Huntington disease

Principal Investigator: Guoyan Zhao (WashU Genetics and Neurology)

Collaborator: Hiroko Yano (WashU Neurosurgery)

Project Details

Description

HD is a monogenic autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT) with an abnormally long polyglutamine tract (PolyQ). Abnormal mHTT accumulation results in a combination of motor, psychiatric and cognitive symptoms and eventually death. Currently, there is no drug to cure or slow the progression of HD. Transcriptional dysregulation is one of the earliest and central pathogenic mechanisms of HD. Altered brain transcription can be related to the manifestation of HD-like symptomsand correcting for HD-induced transcriptional changes can rescue some HD-related phenotypes in mouse models. Additionally, transcriptional dysregulation is relatively well preserved between mouse and human brains; therefore, drugs that work in the mouse HD models may be extrapolated to human patients. In this study, we will take advantage of cell-type-specific gene dysregulation signatures derived from single-nucleus RNA sequencing (snRNA-seq) data of human HD patient postmortem brain tissues and mouse HD models to systematically identifying candidate drugs that may reverse disease gene signatures. Then we will take advantage of our established in vitro striatal and cortical neuron HD model systems to validate their efficacy. Our study will provide novel candidate drugs for the therapeutic development for HD treatment.

2023 Awards


Developing a Molecular Degrader Specific for Misfolded TDP-43

Principal Investigator: Yuna Ayala (Saint Louis University)
Collaborators: Paul Kotzbauer, Timothy Miller, Kathleen Schoch (WashU Neurology), Mingzhou Zhou (Biochemistry and Molecular Biophysics)

Project Details

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.


Assessing the antigen-specificity of CD8 T cells in Amyotrophic Lateral Sclerosis 4

Principal Investigator: Laura Campisi (WashU Pathology & Immunology)
Collaborator: Xiaoxiao Wan (WashU Pathology & Immunology)

Project Details

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.


Targeting a transcriptional co-repressor to prevent photoreceptor degeneration

Principal Investigator: Joseph Corbo (WashU Pathology & Immunology)
Collaborator: Alex Holehouse (WashU Biochemistry and Molecular Biophysics)

Project Details

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.


Closed Loop BCI Manipulation of Sleep State and Slow Waves

Principal Investigator: Aaron Norris (WashU Anesthesiology)
Collaborator: Eric Landsness (WashU Neurology)

Project Details

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.