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Principal Investigator: Song Hong
Organization: LSU HEALTH SCIENCES CENTER
Fiscal Year: 2020
Award: $381,265
Funding agency: National Institute on Aging
ABSTRACT
We are applying for a 1-year supplemental award in response to NIH Notice NOT-AG-20-008 “AD/ADRD-
focused supplements for NIH grants that are not focused on AD/ADRD.” The goal of the parent project of this
supplement is to develop pro-resolving reparative maresin-like lipid mediators encapsulated in microparticles
(MarL-µPs) to resolve chronic inflammation and impaired healing of wounds in aging. The resolution of chronic
inflammation is pivotal for AD/ADRD treatment and appears to involve MarL actions. Thus, we propose in this
project to reduce the MarL-µP size to a nanoparticle range to create MarL encapsulated in nanoparticles
(nanoMarLs) that are able to sustain MarL delivery across the blood-brain barrier (BBB) into the brain. Our
immediate goal for this supplemental project is to develop our innovative nanoMarLs and to determine their
ability to prevent and ameliorate AD pathogenesis. The therapeutic potential of MarLs is currently limited
because MarLs are eliminated from the brain or blood in a few hours, whereas the prevention and amelioration
of AD progression are long-term processes. We have recently developed a MarL carrier that uses a novel
prototype of amino acid (arginine)-based poly(ester amide) protein-mimic (AA-PEA) nanoparticles that have
the potential to sustain MarL delivery across the BBB. AA-PEAs are a new generation of biomaterials that are
biocompatible, biodegradable, and non-toxic. Our working hypothesis is that nanoMarL treatment will resolve
chronic systematic and brain-local inflammation, and may prevent or, at least, ameliorate AD pathogenesis.
Our Aim is as follows. 1A) We will further optimize the nanoMarLs using preparation methods similar to those
described for MarL-microparticles in the active parent award, except with a particle sizeat nano-scale for
delivery across the BBB of AD-model mice. 1B) We will determine the ability of nanoMarLs modulate AD
pathogenesis in AD-model mice. Overall Impact: This supplemental project will identify an innovative
nanoMarL-based strategy and therapeutic that may ameliorate AD pathogenesis by studying bioactions of
MarLs delivered and sustained by AA-PEA nanoparticles. The study is highly translational for the medical care
of AD/ADRD. The proposed work is within the scope of the active parent award that also studies MarLs
delivered and sustained by AA-PEA particles (although the parent award deals with microparticles and chronic
wounds). Thus, this proposal matches the 3 criteria set out in NOT-AG-20-008 for an AD-focused
supplemental grant. It only needs additional parallel studies for preparing and bio-assaying MarL encapsulated
in AA-PEA nanoparticles in AD-model mice, for which we already have expertise. This supplemental award will
allow us to conduct the research, publish novel results, and submit a R01 or U01 application that will further
develop our nanoMarL-based modality to treat AD/ADRD. Our team has synergistic expertise in reparative pro-
resolving lipid mediators, drug delivery biomaterials, and experimental studies of AD, so we are well suited to
undertake this supplemental study.
Terms: <(TNF)-α><AD dementia><AD model><Administrative Supplement><Aging><Alpha Particle Radiation><Alpha Particles><Alpha Radiation><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease dementia><Alzheimer's disease model><Alzheimers Dementia><Alzheimers disease><Amentia><Amides><Amino Acids><Arginine><Assay><Attenuated><Award><Bioassay><Biocompatible Materials><Biologic Assays><Biological Assay><Biomaterials><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood Vessels><Blood-Brain Barrier><Brain><Brain Nervous System><CSIF><CSIF-10><Cachectin><Caring><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Chronic><Cytokine Synthesis Inhibitory Factor><Data><Dementia><Disease><Disease Progression><Disorder><Docosahexaenoate><Docosahexaenoic Acids><Docosahexenoic Acids><Drug Delivery><Drug Delivery Systems><Encapsulated><Encephalon><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Esters><Fibroblasts><Generations><Goals><Grant><Growth Agents><Growth Factor><Growth Substances><Hemato-Encephalic Barrier><Hour><Human><IL-10><IL10><IL10A><Impaired tissue repair><Impaired wound healing><Impairment><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Injections><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><L-Arginine><Macrophage-Derived TNF><Mediator><Mediator of Activation><Mediator of activation protein><Medical><Methods><Mice><Mice Mammals><Modality><Modern Man><Monocyte-Derived TNF><Motility><Murine><Mus><NIH><National Institutes of Health><Natural regeneration><Organ><PDGF-BB><Parents><Particle Size><Pathogenesis><Phenotype><Preparation><Prevention><Primary Senile Degenerative Dementia><Process><Production><Progenitor Cells><Proteins><Proteins Growth Factors><Publications><Publishing><Regeneration><Research><Resolution><Risk Factors><Role><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States National Institutes of Health><VEGF><VEGFs><Vascular Endothelial Growth Factors><Work><Wound Repair><abnormal tissue repair><aged><alzheimer model><aminoacid><aqueous><base><biocompatibility><biological material><biological signal transduction><biomaterial compatibility><bloodbrain barrier><cell motility><chronic skin wound><chronic wound><cytokine><delayed wound healing><dementia of the Alzheimer type><effective therapy><effective treatment><experience><experiment><experimental research><experimental study><healing><improved><injury and repair><innovate><innovation><innovative><lipid mediator><macrophage><mouse model><multidisciplinary><murine model><nano meter scale><nano meter sized><nano particle><nano scale><nano-sized particle><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><novel><parent project><particle><platelet-derived growth factor BB><prevent><preventing><primary degenerative dementia><prototype><regenerate><regenerative><response><restoration><senile dementia of the Alzheimer type><social role><stem cells><tissue wound><vascular><wound><wound healing><wound resolution><wounding><wounds><α Particles>