2024 Transformative Neuroscience Pilot Grant Awards
The UVA Brain Institute offers a seed funding program for transformative neuroscience research projects. The purpose of the program is to tackle important questions, promote interdisciplinary collaboration, and perform groundbreaking work that will enhance our research enterprise.
Awarded applications were selected after two rounds of review based on 1) Scientific Merit – Significance, Innovation, Approach, Investigators; 2) Potential for scientific impact and future external funding; and 3) Potential impact of the pilot award on the project and team. A total of 20 applications were received for the second cycle. Each written application was initially scored by two or more internal reviewers, and ten finalist teams were invited to pitch their project to a panel of peer reviewers from across the UVA neuroscience community. Both initial scores from written review and pitch scores were considered to determine awardees.
2024 Cycle 2 (Fall) Awardees
Impact of Psilocybin on Prolonged Grief
Kim Penberthy, PhD - Department of Psychiatry & Neurobehavioral Sciences, Patrick Finan, PhD - Department of Anesthesiology; Nassima Ait-Daoud Tiouririne, MD - Department of Psychiatry & Neurobehavioral Sciences
This study investigates the use of psilocybin-assisted therapy as a novel treatment for Prolonged Grief Disorder (PGD), a condition characterized by severe and persistent emotional distress following the loss of a loved one. By assessing the feasibility and preliminary efficacy of psilocybin in reducing grief symptoms, this research aims to explore new therapeutic approaches for individuals unresponsive to conventional treatments, potentially transforming the landscape of mental health care for grief-related conditions. Findings from this study will provide critical data to inform larger-scale clinical trials.
Refining MR imaging and analysis methods in the prairie vole to uncover functional differences in the brain of high care fathers
Jessica Connelly, PhD - Department of Psychology; Per Sederberg, PhD - Department of Psychology; Alev Erisir, MD, PhD - Department of Psychology; Jamie Morris, PhD - Department of Psychology
Much of what we know about the impact of the early rearing environment on the developing brain is derived from common rodent models in which the mother provides most, if not all, of the early care. The use of these models and the sparsity of directly translatable neuroscientific methods has limited our ability to apply this knowledge to humans. We have molecularly characterized the impact of early rearing in a biparental rodent model and uncovered a critical role for fathers in male brain development. We seek to use this model to establish imaging methods for translational work in human neurodevelopment.
Uncovering the Molecular Mechanism of Early-Life Infection on Brain Development Using Model Organisms
Sarah Siegrist, PhD - Department of Biology; Michelle Bland, PhD - Department of Pharmacology
Enteric infections in early childhood lead to cognitive impairment, but how such infections disrupt brain development is unknown. We have discovered that enteric infection dramatically reduces proliferation of neural stem cells in Drosophila larvae. Fruit flies and humans share common immune and neural developmental pathways; therefore, we propose to use Drosophila as a genetic model organism to identify mechanisms by which gut infections disrupt brain development.
Computational Biomechanics Simulator of Neuro-Endovascular Surgery to Predict Device Performance
Ryan Kellogg, MD - Department of Neurosurgery; Matthew Panzer, PhD - Department of Mechanical & Aerospace Engineering
Our project seeks to enhance neuroendovascular surgery for stroke treatment, where catheters and wires are navigated through blood vessels to treat patients. By employing advanced computational simulations, we aim to predict device performance in patients, improving both speed and safety of surgeries. Ultimately, our framework will identify key anatomical features that influence procedure difficulty and predict the best surgical approach for each patient.
Discovery of a Novel Role for Sarm1 in Early Protective Schwann Cells After Injury
Chris Deppmann, PhD - Department of Biology; Sarah Kucenas, PhD - Department of Biology
Peripheral nerve injuries affect millions worldwide, often leading to lifelong disability. This research proposal aims to elucidate the role of a novel Schwann cell state, termed the Protective Associated Schwann Cell (PASC), in the early events following peripheral nerve injury. By unraveling the molecular signature and functional properties of PASCs, this study will contribute to the development of more effective strategies for treating peripheral nerve injuries, ultimately improving health outcomes associated with peripheral neuropathies.
APOE Genotypes Shaping Lipid and Protein Interactions during Tau Propagation in Pathogenesis of Alzheimer's disease
Lulu Jiang, MD, PhD - Department of Neuroscience; Huan Bao, PhD - Department of Molecular Physiology and Biological Physics
Our project aims to investigate how different Apolipoprotein E (APOE) genotypes—APOE2, APOE3, APOE4, and the protective APOE3 Christchurch mutation—influence the spread of aggregated tau proteins, a key driver of Alzheimer’s disease. Using a 3D neuron-glial brain model derived from patient stem cells, we will explore how APOE variations affect interactions between lipids, proteins, and RNA that contribute to disease progression. The findings may provide new insights into Alzheimer’s mechanisms and support the development of personalized therapeutic strategies.
Using Base Editing to Correct SCN8A variants and Prevent Seizures in SCN8A Epileptic Encephalopathy
Manoj Patel, PhD - Department of Anesthesiology; Charles Farber, PhD - Department of Genome Sciences
De novo mutations of the Na channel gene SCN8A, coding the Nav1.6 Na channel isoform, cause a terminal form of early-infantile epileptic encephalopathy. Current treatment options are limited to pharmacology and are not very effective. Base editing gene therapy techniques provide a novel, groundbreaking, precision medicine approach to correct the underlying defective mutation, resulting in a cure for this devastating disease.
2024 Cycle 1 (Spring) Awardees
A Novel Rewarding Food Consumption Circuitry Targeted by the Next Generation Weight-Loss Drugs
Ali Güler, PhD - Department of Biology, John Campbell, PhD - Department of Biology
This proposal presents a novel approach to mapping the neural circuits involved in overeating and obesity revealed by the glucagon-like peptide-1 receptor (GLP1R) agonists. Hailed as the "Breakthrough of the Year'' by Science magazine, these agents, the likes of Ozempic and Mounjaro, are revolutionizing the management of metabolic disorders. Our aim is to deepen the understanding of the neuronal circuits that curb hedonic eating (eating beyond the body's energy needs) and use this insight to provide platforms to refine weight loss medications.
Brain microvascular pericyte pathology linking Alzheimer's Disease and Type II Diabetes
Shayn Peirce-Cottler, PhD - Department of Biomedical Engineering, Ukpong Eyo, PhD - Department of Neuroscience
Type II Diabetes is a major risk factor for Alzheimer’s Disease, and we hypothesize that these two diseases are connected through the smallest blood vessels in the brain, the capillaries. Our study will test the hypothesis that both diseases fundamentally disrupt the connections between the cells that form the brain capillaries, causing leaky capillaries and dysregulated blood flow, both of which contribute to impaired brain function. We will study how cell connections in capillaries become disrupted over time and identify strategies to prevent this from happening in Alzheimer’s Disease and Type II Diabetes and when both diseases are present.
Glial-regulated mechanisms of aberrant axonal outgrowth in Alzheimer's Disease across species
Jaeda Coutinho-Budd, PhD - Department of Neuroscience, Elise Cope, PhD - Department of Neuroscience
Alzheimer’s Disease (AD) is a neurodegenerative disease that occurs in the aging population, yet many genes with prominent roles in development are upregulated in the AD brain. Aberrant axonal growth near amyloid plaques was first reported decades ago, and numerous axon guidance and growth factors have been found to be dysregulated in AD, but the extent of how and where these molecules act in AD remains ambiguous to this day. We propose to develop new in vivo Drosophila genetic tools to test mechanistic questions quickly and translate these findings directly into a novel mammalian model to explore the molecular underpinnings of this understudied, yet important phenomenon in AD.
Toward Non-Invasive Gene Therapy and Liquid Biopsy for Childhood Neurodevelopmental Disorders with Transcranial Focused Ultrasound
Sameer Bajikar, PhD - Departments of Cell Biology and Biomedical Engineering, Natasha Sheybani, PhD - Department of Biomedical Engineering
In this Brain Institute Transformative Neuroscience grant, we will explore the use of focused ultrasound (FUS) for localized blood brain barrier opening to non-invasively deliver gene viral therapy to models of Rett syndrome, a severe childhood neurological disorder. To date, no studies have leveraged FUS in Rett syndrome despite an urgent clinical need for less invasive treatments, gene therapy dose de-escalation, and improved biomarkers. We will assess the use of FUS to (1) deliver gene therapy in a titratable fashion and (2) amplify peripheral bioavailability of CNS-derived biomarkers that can inform risks of overtreatment in gene therapy strategies for Rett.
Investigating anxiety-related variability in brain structure-function coupling during adolescence
Stefanie Sequeira, PhD - Department of Psychology, Aiying Zhang, PhD - School of Data Science
Anxiety disorders are the most common mental health disorders affecting children and teens, and up to half of youth who receive treatment for an anxiety disorder do not fully benefit from treatment. To improve treatment, we must deepen our understanding of how the diverse symptoms and behaviors that characterize different anxiety disorders in youth develop. Recent advancements in brain imaging techniques offer promising avenues for advancing this understanding. Led by two new faculty members in Psychology and Data Science at UVA, this project uses innovative methods of combining brain data and clinical and behavioral assessments to examine how brain structure and function is linked to the development of different anxiety-related symptoms and behaviors throughout adolescence in over 10,000 U.S. youth recruited for the Adolescent Brain and Cognitive Development Study. This project will help us better understand the complexity of youth anxiety, with the potential to influence how we think about and design treatments for anxiety in children and teens.
Inceptor, brain insulin resistance and postpartum depression
Heather Ferris, MD, PhD - Division of Endocrinology and Metabolism, Jennifer Payne, MD - Department of Psychiatry and Neurobehavioral Sciences
Post-partum depression is a potentially life-threatening condition, however the causes are poorly understood. Both abnormal estrogen sensitivity and insulin resistance are risk factors for post-partum depression. We will determine if a protein called Inceptor, which is estrogen-regulated and a driver of insulin resistance, is the molecular link between insulin resistance and post-partum depression.
Developing and Validating a Remotely Administered, Digital, Gait-Based Marker to Predict Future Cognitive Decline in Patients with Pediatric-Onset Multiple Sclerosis
Nick Brenton, MD - Department of Neurology, Laurie Brenner, PhD - Department of Neurology, Laura Barnes, PhD - Department of Systems and Information Engineering
Pediatric-onset multiple sclerosis (POMS) patients are at high risk for cognitive impairment; however, there are no current measures to predict those at highest risk, thus limiting our ability to identify, implement, and study interventions that could prevent cognitive decline. In our preliminary work, we show that six-minute walk gait speed trajectories (6MWGST) near the time of diagnosis can predict those POMS patients at risk for future cognitive decline. Our current proposal seeks to a) validate the 6MWGST as a prediction tool for future cognitive decline in POMS by confirming our preliminary findings using a detailed assessment of neurocognitive function and b) develop this outcome for remote administration to facilitate future multicenter implementation and inclusion of rural/underserved patients.
Ambulatory Sleep Monitoring in Persons with Dementia and Caregiver Dyads
Carol Manning, PhD - Department of Neurology, Mark Quigg, MD - Department of Neurology
In the US, unpaid caregivers provide the majority of care for people with dementia. They experience significant burden as the result of stress, mood disorders, financial pressure, lost work time, and illness, and one critical contributor to burden is sleep disturbances. Thus, our long-term goal is to design sleep interventions to protect caregiver health and cognition, but first, we must assess affordable and effective ambulatory methods that will enable us to conduct a definitive trial.