Document text
Principal Investigator: Andrew S Mendiola
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $241,530
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY / ABSTRACT
Oxidative stress is a central part of innate immune-induced neurodegeneration in neurological disorders
including multiple sclerosis (MS). However, the molecular mechanisms regulating oxidative stress gene circuits
to promote neurotoxic immune responses remain poorly characterized. Emerging evidence supports a role for
the epigenome in tightly regulating immune cell gene activity in MS. Yet, the epigenomic landscape and function
in prooxidant, neurotoxic central nervous system (CNS) innate immune cells in MS remains unknown. Thus,
discovery of drugs capable of selectively suppressing immune-driven neurodegeneration has been hindered by
lack of molecular understanding of neurotoxic functions of CNS innate immune cells. The ultimate goal of this
project is to define the regulatory landscape of prooxidant immune cells and identify mechanisms that translate
epigenetic aberrations into innate-immune driven neurodegeneration for devising novel therapeutic interventions
for MS. Our preliminary data discovered a molecular convergence of neurotoxic microglia and peripheral
macrophages to a core oxidative stress gene signature in MS model. By applying an innovative experimental
design with cutting-edge methods, this proposal aims to define the epigenetic and transcriptional components of
oxidative stress-producing innate immune cells in a mouse model of neuroinflammation for MS through unbiased
profiling of the open chromatin landscapes (Aim 1) and histone modifications (Aim 2). These molecular
characterizations will identify key MS-related regulatory elements that will be functionally validated in vitro and
in vivo with CRISPR interference assays (Aim 3). This project will provide a foundational epigenomic outlook on
the molecular circuits governing prooxidant, neurotoxic immune responses in neuroinflammatory disease, and
the research outcomes may reveal candidates for the development of new treatments for innate immune-
mediated oxidative injury in MS and related conditions. The comprehensive training plan will enable the PI to
achieve his career goal of launching a successful independent research laboratory dedicated to studying
epigenomic mechanisms contributing to immune dysfunction in MS for targeted treatments. The MOSAIC UE5
mentoring, leadership, and diversity training will facilitate his transition to independence and enable the PI to
enhance diversity in the biomedical workforce in the R00 phase and beyond. As a mentee in Dr. Katerina
Akassoglou’s laboratory, a leader in neurovascular and immune mechanisms of MS pathogenesis, at the
esteemed academic environment of Gladstone Institutes and University of California, San Francisco, the PI will
obtain new training in functional epigenomics and CRISPR genome engineering during the K99 phase. The PI’s
training and career development will be bolstered through an advisory committee of faculty with related expertise;
and the PI’s participation in didactic activities such as coursework in epigenomics and seminars, will collectively
allow the PI to complete this project and integrate these approaches for making meritorious contributions to the
fields of MS and epigenomics in future independent research.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Active Oxygen><Advisory Committees><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><CNS Nervous System><CRISPR><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/Cas system><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><California><Candidate Disease Gene><Candidate Gene><Cell Body><Cells><Cellular Immune Function><Central Nervous System><ChIP assay><Chromatin><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats interference><Co-culture><Cocultivation><Coculture><Coculture Techniques><Communities><Complex><Coupled><Data><Data Set><Dedications><Degenerative Neurologic Disorders><Development><Disease><Disease Progression><Disorder><Disseminated Sclerosis><Drugs><EAE><Elements><Enhancers><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Experimental Designs><Expression Signature><FISH Technic><FISH Technique><FISH analysis><FISH assay><Faculty><Failure><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><Future><Gene Down-Regulation><Gene Expression Profile><Gene Targeting><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genome engineering><Genomics><Goals><Histones><Hortega cell><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><In Vitro><Infiltration><Inflammation><Inflammatory><Innate Immune Response><Innate Immune System><Innate Immunity><Intervention><Intervention Strategies><Investigation><Investments><Laboratories><Laboratory Research><Leadership><Link><MS treatment><Macrophage><Macrophage Activation><Maps><Mediating><Medication><Medulla Spinalis><Mentors><Methods><Mice><Mice Mammals><Microglia><Modeling><Molecular><Molecular Interaction><Multiple Sclerosis><Murine><Mus><Mφ><NADPH Oxidase><Native Immunity><Natural Immunity><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Outcomes Research><Oxidative Regulation><Oxidative Stress><Oxidative Stress Induction><Oxygen Radicals><Pathogenesis><Pathogenicity><Pathologic><Peripheral><Pharmaceutical Preparations><Phase><Phenotype><Prevention><Pro-Oxidants><Process><Production><RNA><RNA Expression><RNA Gene Products><Reactive Oxygen Species><Regulatory Element><Regulatory Regions><Relapse><Reporter><Repression><Research><Research Resources><Resources><Ribonucleic Acid><Role><San Francisco><Signal Pathway><Spinal Cord><Task Forces><Testing><Therapeutic><Training><Transcription><Transcription Factor Proto-Oncogene><Transcription Repression><Transcription factor genes><Transcriptional Repression><Translating><Universities><advisory team><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><autoimmune encephalomyelitis><biological adaptation to stress><brain control><brain tissue><candidate identification><career><career development><cell type><chromatin immunoprecipitation><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><derepression><developmental><drug/agent><epigenetically><epigenome><epigenomics><gene expression pattern><gene expression signature><gene locus><gene repression><gene signatures><genetic locus><genetic regulatory element><genetic signature><genomic location><genomic locus><gitter cell><histone modification><host response><immune function><immune system response><immunoresponse><in vivo><innovate><innovation><innovative><insular sclerosis><interventional strategy><loss of function><mesoglia><microglial cell><microgliocyte><mouse model><multiple sclerosis therapy><multiple sclerosis treatment><murine model><neural degeneration><neural inflammation><neuro-vascular><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuronal><neuronal degeneration><neuroprotection><neuroprotective><neurotoxic><neurovascular><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oxidative damage><oxidative injury><perivascular glial cell><prevent><preventing><programs><promoter><promotor><reaction; crisis><repressing CRISPR-dCas9 system><single molecule><social role><stress response><stress; reaction><therapeutic candidate><therapeutic target><transcription factor><transcriptional profile><transcriptional signature>