2015 Pilot Projects
Descriptions and progress of each award can be found in the project details.
Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty click on their names below.
Fixing the Broken Clock: Optogenetic methods to restore circadian rhythms in a mouse model of Alzheimer’s Disease
Principal Investigator: Erik Musiek (WashU Neurology)
Collaborators: Erik Herzog (WashU Biology)
Disturbances of the sleep-wake cycle and circadian rhythms, the 24-hour oscillations which govern many aspects of bodily function, are associated with aging and are common in many neurodegenerative diseases, including Alzheimer’s Disease (AD). Emerging evidence strongly suggests that disrupted sleep and circadian rhythms can lead to increased accumulation of amyloid-beta (Aβ), a peptide key to the pathogenesis of AD. Aβ levels in the brain also show a clear day-night rhythm which is tied to the sleep/wake cycle. Circadian and sleep rhythms are generated by the master clock of the body, the suprachiasmatic nucleus (SCN) of the hypothalamus. SCN function declines with age in mice and humans, leading to disrupted rhythms. While age- and disease-related declines in sleep and circadian function have been hypothesized to contribute to neurodegeneration, no methods to specifically manipulate these circadian rhythms have been available. We propose to use optogenetics, a method of stimulating neuronal activity in the brain using light, to stimulate or suppress neurons in the SCN of mouse models of AD. We will determine if acutely altering the firing of the SCN, and thus the circadian rhythms of the animal, can change the dynamics of Aβ levels in the brain. We will also determine if properly-timed optogenetic activation of SCN can rejuvenate the impaired circadian rhythms in mouse models of AD. We hope to create a novel method of “fixing the broken clock” which can be applied across neurodegenerative disease models, in order to understand how circadian function impacts neurodegeneration.
Grants and Awards
“Circadian Regulation of MemoryDuring Alzheimer’s Disease Pathogenesis”
NIH/NIA 5R01AG063834 (PI, Kress)
Public Health Relevance Statement, Project Narrative: Cognitive decline is the defining feature of Alzheimer’s disease. There are no effective treatments to slow the progression of Alzheimer’s disease. This project has the potential to identify new treatments by studying the relationship between the circadian system and cognitive function during Alzheimer’s disease progression.
“Resetting the Clock in Alzheimer’s Disease”
2017 McDonnell Center for Systems Neuroscience Small Grant Award, Washington University in St. Louis (PI, Kress)
Updated April 2021
Mechanisms of neonatal seizures in a mouse model of term-equivalent cerebral hypoxia-ischemia
Principal Investigator: Michael Wong (WashU Neurology)
Collaborator: Rafael Galindo (WashU Neurology)
Neonatal cerebral hypoxia-ischemia (HI) is a major cause of seizures in the newborn period as well as a very important cause of symptomatic infantile and childhood epilepsy later in life. However, the biological mechanisms that lead to neonatal seizures and subsequent development of epilepsy in this patient population remains poorly understood. Furthermore, reliable animal models to systematically study clinical and electrographic seizures during and after neonatal HI are lacking. Utilizing in vivo real-time neonatal electroencephalography (EEG) this pilot project first aims at developing a technique for the identification and characterization of rodent neonatal seizures during and after neonatal HI. A second aim of this project is to better understand the biological mechanisms involved in acute and chronic seizure generation. Specifically, we will investigate whether depletion of SARM protein or overexpression of NMNAT proteins will decrease acute, subacute and chronic seizures following HI. Alteration in the metabolic homeostasis of ischemic immature neurons is known to adversely affect baseline neuronal activity, promote neuronal degeneration and affect early network organization resulting in overall decreases in seizure threshold thus increasing epilepsy risk. SARM and NMNAT are two proteins involved in the generation of NAD+, an essential molecule involved in energy metabolism. Studies by Rafael Galindo demonstrate that SARM depletion or NMNAT upregulation result in significant decreases in acute mouse pup mortality during brain hypoxia-ischemia, decrease neuronal cell death and total brain tissue injury in brain regions that are known to trigger seizures. Therefore, the above effects by SARM and NMNAT may decrease the risk for seizure generation and may help further elucidate the biological pathways involved in epileptogenesis associated with neonatal birth asphyxia.
Grants and Awards
“Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury”
NIH/NINDS R01NS12234 (PI, Galindo; Co-investigator, Wong)
Public Health Statement: NARRATIVE Human chorionic gonadotropin (hCG) is a placentally derived hormone with beneficial properties against the effects of newborn cerebral injury. Using a mouse model of neonatal hypoxia- ischemia, this study proposes to explore the neurobiological mechanisms responsive for the anti- degenerative function of this hormone in the injured preterm and term brain. This study is projected to advance our understanding of hCG receptors in the immature brain with the ultimate intend to develop new treatment strategies for the devastating neurological consequences of birth asphyxia.
“Neurofunctional effects of NMNAT overexpression and SARM depletion in newborn hypoxia-ischemia”
McDonnell Center for Cellular and Molecular Neurobiology (PI, Galindo)
“A mouse model of infantile spasms in tuberous sclerosis”
NIH/NINDS R21 NS104522-01 (PI, Wong)
Public Health Relevance Statement: Infantile spasms (IS) is a developmental epilepsy syndrome of infancy due to a variety of genetic and acquired causes and is strongly associated with a poor long-term neurological prognosis, including intellectual disability, autism, and chronic epilepsy. Tuberous Sclerosis Complex (TSC) is a common genetic cause of IS and is often viewed as a model disease that has mechanistic and therapeutic relevance to other developmental brain disorders. The research in this grant aims to develop a novel animal model of IS in TSC, which should have important future clinical and translational applications for investigating mechanisms and identifying novel therapeutic targets for IS.
Rensing N, Johnson KJ, Foutz TJ, Friedman JL, Galindo R, Wong M. Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a moue model of tuberous sclerosis complex. Epilepsia 2020; 61:879-891.
Rensing, N, Moy, B, Friedman, JL., Galindo, R, Wong, M. Longitudinal analysis of developmental changes in electroencephalography patterns and sleep-wake states of the neonatal mouse. PLoS ONE, 13 (11), art. no. e0207031, (2018).
Updated April 2021
MicroRNA regulation of dendritic cell function in an animal model of multiple sclerosis
Principal Investigator: Gregory Wu (WashU Neurology)
Collaborator: Timothy Miller (WashU Neurology)
Multiple Sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS) that is a leading cause of disability in young adults. While cellular and molecular immune targets are highly promising for the development of MS therapeutics, specific mechanisms by which the immune system coordinates attacks within the brain and spinal cord remain unclear. Dendritic cells (DCs) are a special class of immune cells distributed throughout the body that coordinate immune responses and are regarded as critical for the initiation and maintenance of autoimmune diseases. DCs have been identified from studies on MS and its animal model, experimental autoimmune encephalomyelitis (EAE), as crucial organizers of immune responses during neuroinflammation. Our goal is to identify the molecular features of DCs that promote inflammatory changes during EAE. We have examined DCs for their expression pattern of micro-RNAs – small fragments of genetic material that regulate the function of individual cells and are highly amenable to therapeutic intervention. We identified a micro-RNA signature of DCs during EAE and plan to test whether specific micro-RNAs regulate entry of DCs into the nervous system during disease. We will also examine the relation between the micro-RNA signatures of DC and microglia, immune cells that reside within the CNS. Exploring this mechanism of CNS injury mediated by DCs will pinpoint potential targets for therapy, leading to opportunities for the development of a possible micro-RNA-based treatment for patients with MS.
Hoye M.L., Archambault A.S., Wynne T.M., Oetjen L.K., Cain M.D., Klein R.S., Crosby S.D., Kim B.S., Miller T.M., and Wu G.F. MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis. Immunology. 2018 Sep;155(1):112-122.
Updated April 2021
The role of DNA methylation in Huntington’s disease
Principal Investigator: Hiroko Yano (WashU Neurosurgery)
Collaborator: Ting Wang (WashU Genetics)
Our long-term goal is to discover therapeutic strategies targeting abnormal gene regulation causing neuronal dysfunction and death in Huntington’s disease (HD), a progressive and fatal neurodegenerative disease with no cure to date. Early in the course of disease progression, brains of HD patients and mice show abnormal gene expression, which is thought to play a critical role in disease pathogenesis. Recent studies using disease models have identified extensive changes in several chromatin modifications, including aberrant DNA methylation and histone modifications, which can alter gene expression and potentially contribute to HD pathogenesis. However, we still do not know which chromatin modifications play a dominant and causal role in neurodegeneration in HD, which has significant implications for therapy development. Based on our preliminary results demonstrating the important role of DNA methylation pathways in the death of HD neurons in culture, we hypothesize that the mutant HD protein triggers aberrant DNA methylation, thereby causing dysregulation of genes important for neuronal survival; therefore, DNA methylation pathways can be therapeutically manipulated to restore normal gene expression and protect neurons from HD-mediated neuronal death. The objective of this project is to determine how manipulation of DNA methylation pathways causes neuroprotection. Successful completion of these studies will advance our molecular understanding of gene regulation in HD neurons and lead to the development of new therapeutic strategies to halt disease progression in HD and, potentially, in other progressive neurodegenerative diseases in which aberrant DNA methylation plays a role.
Grants and Awards
“Epigenetic therapy for Huntington’s disease”
Spring 2018 LEAP Inventor Challenge Award, Washington University in St. Louis (PI, Hiroko Yano)
Our goal is to develop an effective neuroprotective therapy that targets a newly discovered and critical epigenetic mechanism—DNA methylation—in Huntington’s disease (HD). Our therapeutic target is the family of DNA methyltransferases (DNMTs), enzymes that catalyze methylation of DNA and thereby regulate gene expression. In this project, we test brain bioavailability and pharmacokinetics of systemically administered DNMT inhibitors in mice and identify a treatment with favorable pharmacological properties.
“Role of DNA methyltransferases in Huntington’s disease pathogenesis”
FY19 Small Grants Program from McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis (PI, Hiroko Yano)
The goal of this project is to identify the role of DNA methyltransferases (DNMTs), DNMT1 and DNMT3A, in neurodegeneration and disease progression in Huntington’s disease in vivo by ablation of DNMT genes in HD mice through genetic cross of DNMT conditional knockout mice with HD mouse models.
“Epigenetic and mRNA Profiling of Striatopallidal Neurons in Huntington’s Disease”
NIH/NINDS R21 NS096603 (PI, Yano)
The goal of this project is to identify critical epigenetic changes causing abnormal gene regulation and neurodegeneration in vivo in striatopallidal medium spiny neurons, the primary cell type at-risk in Huntington’s disease.
“Role of DNA methyltransferases in Huntington’s Disease”
NIH/NINDS R01 NS111014 – 01A1 (PI, Yano)
NIH/NINDS 5R01NS111014-02 (PI, Yano)
Public Health Relevance Statement, NARRATIVE: Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a known genetic mutation, but how this mutation causes neurological symptoms as well as the dysfunction and death of specific neurons remains unclear. Here we will test the hypothesis that an abnormality in a critical epigenetic mechanism involving DNA methyltransferases contributes to HD pathogenesis. This study will identify a novel epigenetic mechanism driving HD neurodegeneration. The findings will lay the foundation for the development of novel therapies that target DNA methyltransferases in HD and potentially other neurodegenerative diseases.
“Methods of treating neurodegenerative disorders comprising DNA methyltransferase inhibitors.”
PCT/US2017/037276 with international rights filed: 6/13/2017
Patent application (WO2017218551A1) published: 12/21/2017
US 10842807B2 (Yano H and Kim A)
Patent granted: November 24, 2020
Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, Pondugula S, Swamidass, SJ, Wang T, Kim AH, Yano H. Inhibition of DNA methyltransferases blocks mutant huntingtin-induced neurotoxicity. Sci Rep.;6:31022, (2016).
Pan Y, Zhu Y, Yang W, Tycksen E, Liu S, Palucki J, Zhu L, Sasaki Yo, Sharma MK, Kim AH, Zhang B, and Yano H. The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity. J Biol Chem 2018, 293(30):11850-11866.
Updated April 2021