2020 Pilot Projects
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.
Role of satellite glia cells in chemotherapy-induced neuropathy
Principal Investigator: Stefanie Geisler (WashU Neurology)
Collaborator: Valeria Cavalli (WashU Dept. of Neuroscience)
Neurodegeneration has classically focused on neurons, however major recent breakthroughs led to the realization that glial cells in the brain also play an essential role in the development and progression of neurodegenerative diseases. In the peripheral nervous system, neurons are also closely surrounded by glial cells, but less is known about the peripheral neuron-glia interactions and the involvement of peripheral glia in neurodegenerative diseases. We propose to fill this major gap in knowledge by identifying the molecular signature of a specialized peripheral glia, i.e., satellite glia cells, which completely surround sensory neurons, in a mouse model of peripheral neuropathy. Peripheral neuropathies are the most common neurodegenerative diseases affecting more than 20 million people in the USA alone. Chemotherapy, including treatment with the highly effective drug bortezomib (BTZ), is a frequent cause of peripheral neuropathy. BTZ-induced neurotoxicity stands out among different types of chemotherapy-induced neuropathy as it can be extremely painful. This pain can last long after treatment has ended and significantly reduce the quality of life of patients. Pain is frequently associated with degeneration of intraepidermal nerve fibers. However, surprisingly, such loss has not been observed in most patients treated with BTZ or in our BTZ-induced neuropathy mouse model. Rather, our preliminary data suggest that satellite glia cells surrounding sensory neurons respond to BTZ treatment by increasing expression of a gene that reflect their activation state. We know that satellite glia cells contribute to pain in several injury models by impacting neuronal excitability and, thus, nociceptive threshold. But whether and how satellite glia contribute to pain in peripheral neuropathies has not been explored. Here, we aim to understand how SGC respond to BTZ treatment with the goal to establish mechanistic insights that can be exploited therapeutically to alleviate pain and other sensory abnormalities.
Microglial Phagocytosis as a Determinant of Neuro-inflammation in AD pathogenesis
Principal investigator: Abhinav Diwan (WashU Medicine)
Collaborators: Carolina Soriano Tarraga (WashU Psychiatry), Oscar Harari (WashU Psychiatry)
In Alzheimer’s disease, abnormal aggregates of a protein called Abeta accumulate in the brain tissue in the spaces in between cells. These aggregates are believed to be toxic to the neurons and trigger changes that lead to dementia. Microglia are immune cells that patrol these spaces and take up these abnormal protein aggregates via a process called phagocytosis. Our studies as well as others’ work points to impaired phagocytosis by the microglia in brains with advanced Alzheimer’s disease, which leads to an inability to clear these abnormal protein aggregates. In this pilot proposal, we will study how impairment of phagocytosis in microglia affects other cells in the brain. We will employ genetic manipulation in mice to disable two key genes involved in phagocytosis, namely Mer and Axl, in microglia in mouse models of Alzehimer’s disease. Thereafter, we will utilize state-of-the art genetic sequencing to understand the effects of these manipulations on microglia, as well as on other brain cell types. These data will be compared with the information generated from genetic sequencing on human brain tissue from patients with Alzheimer’s disease to understand mechanisms of disease progression that are common between this animal model and human disease. Understanding these mechanisms will be critical in developing targeted therapies to prevent and/or treat Alzheimer’s disease.
Defining the molecular basis for inhibiting LRP1-mediated cellular propagation of pathogenic tau
Principal Investigator: Thomas Brett (WashU Medicine)
Collaborator: Gaya Amarasinghe (WashU Pathology & Immunology)
Cell-to-cell propagation of pathogenic tau is a major mechanism that contributes to spread of neurotoxic tau and neuronal death in Alzheimer’s disease. The low-density lipoprotein receptor-related protein 1 (LRP1) is the major receptor mediating uptake of tau into neurons and, thus, potentially contributing to pathogenic tau propagation throughout the brain. We have identified a viral glycoprotein that can bind LRP1 with high affinity and potently block tau engagement. In this project, we will structural and biochemical methods to characterize LRP1-tau interactions and investigate how the viral glycoprotein can block LRP1-mediated tau spreading. We also expect our studies to develop a framework to design new therapies to inhibit the propagation of pathogenic tau in AD and other dementias.
A synthetic gene therapy approach for Angelman syndrome
Principal Investigator: Jason Yi (WashU Neuroscience)
Collaborator: Susan Maloney (WashU Psychiatry)
Angelman Syndrome (AS) is a debilitating, life-long disorder characterized by intellectual disability, motor issues, sleep disturbances, and epilepsy. AS is caused by the deletion or mutation of the maternal copy of UBE3A, a gene also linked to autism, bipolar disorder, and age-related cognitive decline. Our laboratory recently uncovered a class of inert, synthetic proteins that can modulate the activity of UBE3A. Here, we propose studies to determine if viral delivery of a synthetic protein that potently stimulates the ligase activity of UBE3A can correct behavioral abnormalities in a mouse model of Angelman Syndrome. If successful, our study will provide a new method that may reverse phenotypes in Angelman Syndrome through gene therapy.
Targeting DNMT3A as a therapeutic strategy for Huntington’s disease
Principal Investigator: Hiroko Yano (WashU Neurosurgery)
Collaborator: Andrew Yoo (WashU Developmental Biology), Allegra Petti (WashU Neurosurgery)