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Principal Investigator: Maria Mavrikaki
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $855,196
Funding agency: National Institute on Aging
SUMMARY. This proposal is in response to PAR-21-038: Stephen I. Katz Early Stage Investigator Research
Project Grant. Aging is a major risk factor for the development of cognitive deficits and neurodegenerative
diseases. Understanding the exact molecular mechanisms of brain aging and accelerated brain aging can lead
to the development of novel interventions to delay or potentially reverse brain aging. Environmental factors
including viral infections (such as SARS-CoV-2, the virus that caused the COVID-19 pandemic) have been
shown to be associated with cognitive decline and accelerated brain aging. However, the exact molecular
mechanisms underlying the effects of environmental factors, and specifically COVID-19, on brain aging remain
unknown. Our long-term goal is to identify key factors that induce accelerated brain aging, so that therapeutics
can be developed to delay or reverse brain aging. The overall objective of this proposal is to identify genes and
regulators of gene expression that cause brain aging and accelerated brain aging in COVID-19 patients. Previous
research from our group showed that many microRNAs (miRNAs), which are small non-coding RNAs that induce
an orchestrated regulation of gene expression, are differentially expressed in the aged mouse brain and regulate
aging. Based on those data and our recently published bulk RNA sequencing studies showing molecular
signatures of brain aging in COVID-19 patients, our central hypothesis is that dysregulated gene and miRNA
expression is an important facet of accelerated brain aging. Previous studies using microarray and bulk RNA
sequencing approaches showed that aging induces distinct molecular signatures in the human frontal cortex.
While layer enriched expression signatures have been identified in the human frontal cortex, the spatial
topography of molecular signatures of aging remain largely unknown. Here, we will utilize state-of-the-art spatial
transcriptomic technologies to analyze human frontal cortex sections from healthy individuals across lifespan,
as well as frontal cortex sections from COVID-19 patients (and appropriate controls) to identify spatially distinct
aging-regulated transcriptomic changes. We will investigate the effects of aging-regulated genes on cellular
senescence using in vitro assays. To better understand regulatory mechanisms of aging-regulated gene
expression, we will measure the expression of miRNAs in healthy individuals across lifespan and COVID-19
cases on similar frontal cortex sections and we will identify aging-regulated mRNA targets for candidate miRNAs.
Finally, we will test the potential of miRNAs to accelerate and delay aging using in vitro assays and in vivo mouse
models. These studies are expected to have a significant impact as they will determine novel targets for the
development of therapeutics to delay or reverse brain aging and aging-related neuropathology. This proposal is
highly relevant to public health and to the NIA’s mission of advancing knowledge on the causes of aging
processes and age-associated diseases to extend healthy lifespan.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><AAV vector><AAV-based vector><Acceleration><Adult><Adult Human><Age><Aging><Assay><Autopsy><Binding Sites><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Body Tissues><Brain><Brain Nervous System><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 effect><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cell Aging><Cell Senescence><Cellular Aging><Cellular Senescence><CoV-2><CoV2><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Combining Site><Coronaviridae Infections><Coronavirus Infections><Coronavirus Infectious Disease 2019><Data><Degenerative Neurologic Disorders><Development><Disease><Disorder><Disturbance in cognition><Dysfunction><Encephalon><Environmental Factor><Environmental Risk Factor><Expression Signature><Functional RNA><Functional disorder><Funding Opportunities><Gene Action Regulation><Gene Expression><Gene Expression Profile><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genes><Genetic Transcription><Goals><History><Human><Impaired cognition><In Vitro><Individual><Induced Neurons><Intervention><Intervention Strategies><Investigators><Knowledge><Luciferase Immunologic><Luciferases><Maps><Measures><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Mission><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Neurophysiology - biologic function><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Normal Tissue><Normal tissue morphology><Phenotype><Physiopathology><Play><Public Health><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Recording of previous events><Regulator Genes><Replicative Senescence><Reporter><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Risk Factors><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 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Mutagenesis><Site-Specific Mutagenesis><Small RNA><Spatial Distribution><Targeted DNA Modification><Targeted Modification><Technology><Testing><Therapeutic><Tissues><Transcription><Transcriptional Regulatory Elements><Untranslated RNA><Validation><Ventilator><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><accelerated aging><accelerated biological age><accelerated biological aging><adeno-associated viral vector><adeno-associated virus vector><adulthood><age acceleration><age associated disease><age associated disorder><age associated effects><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age effect><age related effects><age related human disease><age-related disease><age-related disorder><age-related impairment><aged><aged brain><aged mice><aged mouse><ages><aging associated><aging associated mechanism><aging brain><aging effect><aging mechanism><aging pathway><aging process><aging related><aging related mechanism><biological mechanism of age><biological pathways of age><cell type><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 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signature><mouse model><murine model><nCoV2><necropsy><neural function><neurodegenerative illness><neuronal><neuropathologic><neuropathological><neuropathology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><noncoding><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><old mice><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><postmortem><prevent><preventing><promoter><promotor><regulatory 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