2012 — 2016 |
Musiek, Erik Steven |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Circadian Clock Dysfunction as a Mediator of Neurodegeneration
DESCRIPTION (provided by applicant): The goal of this mentored Career Development Award is to facilitate the primary investigator's transition to independence as a physician-scientist studying the molecular mechanisms of neurodegeneration. The proposed research, which will be conducted under the mentorship of Dr. David Holtzman, will examine the potential role of circadian clock genes as master regulators of neuronal oxidative stress and metabolism, and examine the role of the circadian clock in neurodegeneration. Circadian dysfunction is a prominent symptom of many age-related neurodegenerative diseases, including Alzheimer's disease. However, the impact of circadian dysfunction on neurodegenerative disease pathogenesis, if any, is unknown. On a molecular level, circadian rhythms are generated by conserved transcriptional machinery (the core circadian clock) that is present in most cells in the body, including neurons and glia, and oscillates with a 24 hour periodicity. In many tissues, circadian clocks serve as master regulators of metabolism, aging, and oxidative stress, though this has not been demonstrated in the brain. The goal of this project is to test the hypothesis that circadian clock dysfunction contributes to the pathogenesis of neurodegenerative diseases, in particular Alzheimer's disease. In order to test this hypothesis, the effect of genetic deletionof the master circadian clock gene Bmal1 on brain function and pathology will be examined through the following aims: 1) Elucidation of neuropathology changes in Bmal1 knockout mice, and identification of specific signaling abnormalities in clock-regulated pathways which mediate these changes. 2) Examination of the effect of Bmal1 deletion on neuronal metabolism, oxidative stress, and amyloid-beta regulation in living mice using in vivo micro dialysis. 3) Determination of the impact of brain-specific Bmal1 deletion on disease pathogenesis, oxidative stress, and amyloid-beta dynamics in a mouse model of Alzheimer's disease. The proposed experiments are designed to illuminate a possible novel link between circadian clock dysfunction and neurodegeneration, with the ultimate goal of indentifying novel therapeutic targets for age-related neurodegenerative conditions. This training grant will provide the primary investigator with research training which will parallels his clinical focus in dementia, and will ultimately provide a skill set for translation of basic science discoveries into diagnostic and therapeutic strategies for patients with neurodegenerative diseases.
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0.958 |
2015 — 2019 |
Musiek, Erik Steven |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Project 3: Circadian Rhythms in Regulation of Abeta Pathology and Brain Oxidative Stress
Project 3 Project Summary/Abstract Disruption of circadian rhythms in activity, sleep-wake cycle, and other physiologic parameters is a consequence of aging, and occurs prominently in Alzheimer's Disease (AD). While circadian dysfunction is a major cause of morbidity in AD, it is unknown if it contributes to disease pathogenesis. Systemic circadian rhythms in mice and humans are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes peripheral oscillations of core clock genes in all organs with the light-dark cycle. Our preliminary data shows that genetic deletion of core circadian clock genes, which mediate circadian transcriptional oscillations, can cause neuronal oxidative stress and neurodegeneration, suggesting that disruption of whole- animal SCN-driven circadian rhythms might have deleterious effects in AD through clock gene dysregulation. Human pathologic studies suggest that the SCN is a site of neuropathology in AD, though the impact of SCN dysfunction on AD pathogenesis is unknown. The objective of this Project is to test the hypothesis that impaired SCN-mediated circadian rhythms will increase amyloid-beta (A?) pathology, synaptic injury, and oxidative stress in mouse models of AD and in human AD patients. We will examine how lesioning of the SCN, which abrogates systemic circadian rhythms in mice, alters sleep-wake parameters and circadian patterns of cortical and hippocampal gene expression in 2 mouse models of A? accumulation. We will determine if SCN lesioning accelerates A? plaque deposition in these mouse models, and examine if loss of SCN-mediated rhythms affects A?-induced synaptic injury, neuroinflammation, and oxidative damage. Finally, we will examine correlations between circadian patterns in activity (actigraphy) and cerebrospinal fluid markers of oxidative stress and AD pathology in older adults and individuals with preclinical AD. These studies are designed to reveal dysfunction of SCN-mediated circadian rhythms as a contributing factor in AD pathogenesis, suggesting that therapies targeting the circadian system might prevent or delay AD.
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0.958 |
2017 — 2021 |
Musiek, Erik Steven |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Glial Circadian Clock Dysfunction in the Pathogenesis of Alzheimer's Disease
PROJECT SUMMARY/ABSTRACT Role of glial circadian clock dysfunction in the pathogenesis of Alzheimer?s Disease Chronic disruptions of the circadian system, manifesting as sleep disturbances, day-night confusion, and ?sundowning?, are well-described and debilitating symptoms of Alzheimer?s Disease. While circadian disruption has long been considered a consequence of the degenerative process in AD, accumulating human and mouse data suggest that circadian rhythm abnormalities may begin before overt cognitive symptoms, and could play an important contributory role in AD pathogenesis. Circadian rhythms are generated in cells by specific clock genes, which are expressed in neurons and glia throughout the brain and control 24-hour oscillations in transcription. We have discovered that abrogating the function of the circadian clock via deletion of the master clock gene Bmal1 in the brain causes severe gliosis, synaptic loss, neuroinflammation, and age- related neurodegeneration. The circadian clock is particularly robust in glial cells, regulating cellular activation and inflammatory responses in both astrocytes and microglia. Thus, we will address the bidirectional relationship between circadian clock disruption and amyloid-beta (A?)-related pathology in cellular and mouse models of AD, focusing on the function of clock genes in astrocytes and microglia. Using novel methods to interrogate cell type-specific transcription in vivo and in vitro, we will test the hypothesis that A? directly impairs the cellular circadian clocks of astrocytes and microglia in mouse AD models via an oxidative stress-dependent mechanism. We will then determine if cell type-specific Bmal1 deletion in astrocytes and microglia, respectively, will exacerbate neuroinflammation and synapse loss in the APP/PS1 mouse model of AD. We have identified specific circadian-controlled pathways in astrocytes and microglia that may mediate these effects, and will attempt to target these pathways therapeutically to mitigate neuroinflammation and synaptic degeneration in aged APP/PS1 mice.
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0.958 |
2019 |
Holtzman, David M. (co-PI) [⬀] Holtzman, David M. (co-PI) [⬀] Ju, Yo-El S (co-PI) [⬀] Musiek, Erik Steven |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sleep and Circadian Rhythms in Alzheimer Disease: Potential Bi-Directional Relationship With Tau
PROJECT SUMMARY Sleep and Circadian Rhythms in Alzhiemer?s Disease: Potential bi-directional relationship with tau Sleep and circadian rhythm disturbances have long been described in symptomatic Alzheimer?s Disease (AD). Recent studies by our group and others show that these disturbances are detectable years before the onset of cognitive impairment, during the preclinical phase of AD. Our group has shown that modulating the amount of sleep in mice has striking effects on amyloid plaque deposition, as sleep deprivation augments plaque burden while sleep enhancement reduces plaques. Moreover, we have found that levels of A? peptide in the interstitial fluid (ISF) exhibit clear diurnal rhythms which are regulated by the sleep/wake cycle and the central circadian clock, and that disruption of the circadian system and promotes amyloid plaque formation. While amyloid plaque deposition is the first known biomarker change in AD, it appears to be the ability of amyloid plaques to augment tau aggregation and spreading that is directly linked to neurodegeneration and cognitive decline in AD. Tau spreading though the brain, and the effect of A? pathology on tau aggregation, can be modeled by injection of tau-enriched AD brain lysate into the brain of A? plaque-bearing APP knock-in mice. Based on our preliminary data, we hypothesize that sleep disturbance and circadian rhythm disruption may promote tau spreading and aggregation by increasing the release of tau seeding species from neurons. We propose to examine the impact of chronically restricting or increasing sleep on neuronal tau spreading and plaque-induced tau aggregation in mice. Because apolipoprotein E (apoE) strongly influence A? and tau pathology and interacts with sleep, we will elucidate the interaction between APOE genotype, sleep deprivation, and tau spreading and aggregation. Using both genetic and environmental circadian disruption models, we will perform similar experiments to determine the effects of circadian disruption on tau spreading and A?-induced tau aggregation, and explore the interplay between circadian disruption, sleep, and apoE on A? and tau pathology. Finally, we will examine the longitudinal relationship between sleep disturbance, circadian fragmentation, and preclinical A? and tau pathology in humans. We hypothesize a bidirectional relationship between AD pathology and sleep/circadian rhythms, in which AD pathology disrupts sleep/circadian function, while sleep/circadian disruption promotes AD pathology. We will if sleep or circadian rhythm changes are associated with increased future risk of plaque deposition, tau aggregation, or cognitive decline in humans. These studies will elucidate the interaction between sleep, circadian rhythms, and tau aggregation in mice and humans, as well as the role of apoE in that process.
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0.958 |
2020 — 2021 |
Musiek, Erik Steven |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Rev-Erb Proteins in Neuroinflammation and Alzheimer's Disease
PROJECT SUMMARY/ABSTRACT Role of REV-ERB Proteins in Neuroinflammation and Alzheimer?s Disease Circadian rhythm disruption is observed in Alzheimer?s Disease, and emerging data suggests that circadian dysfunction may contribute to the neurodegenerative process. However, mechanisms connecting circadian dysfunction to Alzheimer?s Disease-related neurodegeneration remain unclear. On a molecular level, core circadian clock genes mediate circadian rhythms, and also serve as critical transcriptional and metabolic regulators in a variety of organs, including the brain. We have shown that genetic disruption of the circadian clock by deletion of the master clock gene Bmal1 causes severe gliosis, oxidative damage, and synaptic degeneration in mouse brain, suggesting a link between core clock function and neurodegeneration. We have subsequently found that the deletion of REV-ERB?, a component of the core clock which is directly regulated by BMAL1, also causes spontaneous microglial activation and neuroinflammation. Our data shows that REV- ERB? expression is suppressed in the cortex of amyloid plaque-bearing APP/PS1 mice, a model of Alzheimer?s Disease, and in activated microglia. REV-ERB? and its homolog REV-ERB? are nuclear receptors which, aside from their function in the circadian clock, have been implicated in regulation of inflammation and metabolism. We hypothesize that REV-ERBs serve to link the circadian clock to neuroinflammation and neurodegeneration. We will examine the cell-autonomous function of REV-ERBs in regulating microglial activation and neuroinflammation, and identify transcriptional pathways regulated by REV-ERBs in microglia. We will determine if REV-ERBs control microglial synaptic phagocytosis in the brain via transcriptional regulation of complement genes. Because they are nuclear receptors, REV-ERBs can be manipulated pharmacologically. Thus, we will examine the effects of cell type specific genetic deletion of REV-ERBs, or activation or inhibition of REV-ERB function with small molecule agonists, on neuroinflammation and neurodegeneration in a mouse model of Alzheimer?s Disease. These studies will shed new light on molecular mechanisms linking the circadian clock and Alzheimer?s Disease-related neurodegeneration, and illuminate the novel strategy of directly targeting the circadian clock for neuroprotection.
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0.958 |