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.
Determining the pathogenic role of FGFR3 autoantibodies in idiopathic small fiber neuropathy
Small fiber neuropathy is a disease in which the nerves that transmit painful signals from the body to the brain are dysfunctional. Patients with this disease suffer debilitating symptoms, most notably pain that feels like burning, shocking or stabbing. Emerging evidence increasingly points toward dysfunction of the immune system as a cause of some cases of small fiber neuropathy. In particular, recent work has identified autoantibodies to the Fibroblast Growth Factor Receptor 3 (FGFR3) in some patients with small fiber neuropathy. However, it is unknown whether these autoantibodies are the actual cause of small fiber neuropathy in these patients, or whether another pathological process is at work. Thus, the major goal of this project is to determine whether autoantibodies against FGFR3 do indeed cause small fiber neuropathy. To answer this question, we will use a translational strategy in which we evaluate the ability of patient-derived FGFR3 autoantibodies to produce features of small fiber neuropathy both in vivo and in vitro. The findings of this project will provide much needed insight into the role of FGFR3 autoantibodies in small fiber neuropathy and will provide a critical foundation for the development of novel therapies for this debilitating disease.
Reversibility of amyloid-induced mitochondrial dysfunction in Alzheimer’s disease
Deficiency in brain energy metabolism has long been recognized as a prominent event in the development of Alzheimer’s disease. Recent studies provide new evidence that mitochondrial dysfunction may occur early and in proximity to amyloid deposition, a hallmark of Alzheimer’s disease. In this project, we seek to understand the spatiotemporal relationship between amyloid deposition and mitochondrial metabolic dysfunction through the development and application of first-of-a-kind dual-modal microscopy (i.e., multi-photon fluorescence microscopy of mitochondrial function and amyloid deposition at the cellular level and multi-parametric photoacoustic microscopy of oxygen metabolism at the tissue level) in a mouse model of Alzheimer’s disease. Examination of the potential reversibility of mitochondrial metabolic dysfunction following anti-amyloid therapies may lead to non-invasive imaging biomarkers that predict when such therapies can alter the course of neurodegeneration. Translation of such neuroimaging biomarkers to patients may one day guide therapeutic intervention.
Grants and Awards
“Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer’s Disease”
NIH/NIA 1RF1AG079503-01 (PI, Goyal)
Public Health Relevance Statement, PROJECT NARRATIVE: Data from human studies show that Alzheimer’s disease affects brain metabolism, including glucose and oxygen use, but the details are unclear. In this study, we aim to use new optical imaging techniques to understand how Alzheimer’s disease-related pathology leads to metabolic dysfunction in the live mouse brain at the cellular, tissue and network level. We will then determine if this metabolic dysfunction can be reversed by anti-amyloid treatment, potentially leading to more effective treatments for Alzheimer’s disease.
SARM1 inhibition as a novel therapeutic strategy for Cln1 disease
Neuronal ceroid lipofuscinosis is a fatal genetic disorder that kills children. Its infantile form, also called CLN1 disease has a devastating effect upon the brains of these children. Previous attempts to treat CLN1 disease have proved only partly effective. This is likely because there are underappreciated effects of disease upon the rest of the body that we failed to treat. This includes the nerve fibers, or axons, that control our movements and help us sense the environment. We have recently found that these axons are eliminated as CLN1 disease gets worse. Blocking this axonal pathology is anticipated to provide a more effective treatment for CLN1 disease. Because we know one of the key mechanisms by which axons are lost in many neurodegenerative diseases, we will now test if we are able to block this mechanism in a model of CLN1 disease. We will do this in two different ways, first genetically to gain proof of principle that this strategy may be beneficial. Secondly, we will use gene therapy to specifically suppress axon degeneration. At the end of these experiments we will know whether we can rescue this newly identified axonal feature in a model of CLN1 disease. This will also lend further support for how blocking axon degeneration may be a treatment for other neurodegenerative diseases.
Internet of things (IoT) monitoring of rodent home-cages to understand circadian plasticity
Nearly every organism on Earth, from bacteria to humans, contain a circadian clock. This clock maximizes survival by determining optimal times for processes such as activity, rest, and feeding. In recent decades, circadian disruptions have become common, as more people stay up late consuming internet and other media content or engage in work that requires their waking hours to deviate from the normal light period of the day. Such circadian disruptions have been linked to several diseases, including neurodegenerative diseases such as Parkinson’s, Huntington’s, and Alzheimer’s disease. However, the mechanisms by which disruptions might cause neurodegeneration remain unknown. To explore the link between circadian rhythms and neurodegeneration, we built a system to quantify circadian rhythms across hundreds of mice in their home cages, using a novel cloud-based data collection system. We will leverage the high-throughput nature of this system to understand circadian disruptions and neuronal cell death in mouse models of neurodegeneration. If successful, we hope to predict neurodegeneration from changes in circadian rhythms in mice, and gain insights into the mechanistic links between the two.
DNA methylation in Alzheimer’s disease
Principal Investigator: Oscar Harari (WashU Psychiatry)
Collaborator: Ting Wang (WashU Genetics)
Alzheimer’s disease (AD) is the most common neurodegenerative disease, but currently there is no effective means of prevention or treatment. Age is the major risk factor for AD, but AD is not a normal part of aging. The cause of AD is complex and not specific to a single genetic factor or brain cell-type. DNA methylation is a reversible process that can modulate the expression of genes, without changing the genetic sequence. It varies across the lifespan and its levels are influenced by lifestyle and environmental and genetic factors 11. Through the execution of this project we will study the age-related changes in DNA methylation in AD and in individuals who do not show AD-related brain changes. Our results will provide a better understanding of the molecular mechanisms that drive AD pathogenesis.