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Principal Investigator: HUANG-GE ZHANG
Organization: LOUISVILLE VA MEDICAL MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes.
These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles and
I am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatment
for a diverse but specific group of medical conditions, i.e., inflammation related diseases including widespread
brain inflammation related diseases, obesity, rheumatoid arthritis, nonalcoholic fatty liver disease (NASH), and
cancer. The accumulation of inflammatory cells that release proinflammatory cytokines and chemokines not only
promote brain disease progression such as Gulf War Syndrome but also rheumatoid arthritis, obesity and/or
cancer. These diseases pose special burdens on veterans who depend on the VA for healthcare.
Since receiving my initial Research Career Scientist award, my research group has published more than 60
manuscripts on this subject. Collectively, our findings support continued funding of my team to investigate the
following aims: (1). Develop a therapeutic strategy to target delivery of therapeutic agents to microglia for
treatment of brain inflammation related diseases such as Gulf War Syndrome. Microglia cells respond vigorously
to both chronic disease and acute insults affecting brain function. Targeted delivery of therapeutic agents to
microglia is needed but highly challenging. The results published from my group (Theranostics, 2022,1220-1246,
Cell Host Microbe, 2022, 944-960, and Small 2022, 2105385) provide emerging evidence for the development
of edible exosome-like nanoparticles as a safe delivery system for targeting different tissues including brain
microglial cells, either by systemic or oral administration. (2). Investigate the role of tumor exosomes in
immunosuppression through induction of myeloid-derived suppressor cells, inhibition of dendritic cell
differentiation, and inhibition of activation of NK cell immunotherapy. This approach is supported based on our
published results (Nature Communications. 2017 Feb 17;8:14448, Nature communications. 2015;6:6956). (3).
Exosomes are released from non-tumor cells and we will determine their role in: (a) exosome accumulation in
adipose tissue (Diabetes. 2009 Nov;58(11):2498-505, Hepatology, 2013 57(3):1250-61), we will investigate the
role of adipose tissue exosome-like vesicles in activation of macrophage-induced insulin resistance and induction
of liver NKT cell anergy; and (b) investigate exosomes released from rheumatoid synovial fibroblasts and inhibit
regulatory T cell development. Their role in contributing to damaging joint cartilage will be further investigated.
(4). Based on the results we published as listed below, we will further develop customized exosome-like
nanoparticles from edible plants as therapeutic vehicles to treat/prevent specific disease. (a) Ginger exosome-
like nanoparticles (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner
and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG) to prevent DSS induced
mouse colitis (Cell Host Microbe, 2018, p637-652). Oral administration of oat nanoparticles inhibits brain
inflammation and improves brain memory function of mice fed alcohol by targeting microglial cells (Small 2022,
2105385). We have shown that targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) are
delivered to intestinal macrophages, brain microglia cells (Molecular therapy: 2015, Volume 24, Issue 1, p96–
105), inflammatory tumor sites (Cancer Research, 2015;75:2520-9) by edible and health plant derived ELN.
Broccoli-derived nanoparticle inhibits mouse colitis by induction of tolerogenic gut associated dendritic cells
(Molecular Therapy. 2017), and grape exosome-like nanoparticles induce intestinal stem cells (Molecular
Therapy. 2013 Jul;21(7):1345-57). Collectively, our findings will not only open up a new avenue for investigating
ELNs as a means to protect against the development of inflammation related diseases such as alcohol induced
liver and gut damage, brain and joint inflammation related diseases, but sheds light on studying the cellular and
molecular mechanisms underlying inter-species communication via edible plant-derived nanoparticles.
Terms: <Acute><Address><Adipose tissue><Affect><Ajo><Alcohol Chemical Class><Alcohols><Allium sativum><Antibodies><Antiinflammatory Effect><Antioncogene Protein p53><Atrophic Arthritis><Autoregulation><Avena sativa><Award><Binding><Biology><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Inflammation><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Broccoli><Broccoli - dietary><CAGA><CGLA><Cancers><Cartilage><Cartilaginous Tissue><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Tumor Antigen P53><Chemokine Receptor Gene><Chemotactic Cytokines><Chronic><Chronic Disease><Chronic Illness><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Colitis><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Communication><Complex><Curcumin><DNA><DSS colitis><DSS model><DSS mouse model><DSS-induced acute colitis><DSS-induced colitis><Data><Dendritic Cells><Deoxyribonucleic Acid><Development><Diabetes Mellitus><Diet><Diferuloylmethane><Disease><Disease Progression><Disorder><Disturbance in cognition><Drug Targeting><Drugs><Edible Plants><Encephalitis><Encephalon><Encephalon Diseases><Equilibrium><Fatty Tissue><Fibroblasts><Folate><Folic Acid><Food><Food Plants><Funding><Future><GI microbiome><GI microbiota><Garlic><Gastrointestinal microbiota><Gene Expression><Generalized Growth><Genes><Ginger><Goals><Grapefruit><Grapes><Growth><Gulf War Illness><Gulf War Syndrome><Health><Health Status><Healthcare><Hepatology><High Fat Diet><Homeostasis><Homing><Homologous Chemotactic Cytokines><Hortega cell><IL-22><Immune system><Immunity><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impaired cognition><Inflammation><Inflammatory><Insulin Resistance><Intercrines><Intestinal><Intestines><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><L rhamnosus><L. rhamnosus><Lactobacillaceae><Lactobacillus casei rhamnosus><Lactobacillus rhamnosus><Level of Health><Lipids><Liver><MA387><MRP8><Macrophage><Macrophage Activation><Malignant Neoplasms><Malignant Tumor><Manuscripts><Mediating><Mediator><Medical><Medication><Memory><Metabolic><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Microbe><Microglia><Modeling><Molecular><Molecular Interaction><Murine><Mus><Myeloid-derived suppressor cells><Mφ><NAFLD><NK Cell Activation><NK cell immunotherapy><NK cell-based immunotherapy><Natural Killer Cell Activation><Natural Killer Cell Immunotherapy><Nature><Nerve Degeneration><Neuroimmune><Neuron Degeneration><Non-Polyadenylated RNA><Oats><Obese Mice><Obesity><Oncogene Products><Oncogene Proteins><Oncoprotein p53><Oncoproteins><Oral Administration><Oral Drug Administration><Outcome Study><P53><PTSD><Pathway interactions><Patients><Persian Gulf Syndrome><Pharmaceutical Preparations><Phosphoprotein P53><Phosphoprotein pp53><Physiologic><Physiological><Physiological Homeostasis><Plants><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Preventative strategy><Prevention strategy><Preventive strategy><Probiotics><Progenitor Cells><Promoter Regions><Promotor Regions><Protein TP53><Pteroylglutamic Acid><Publishing><RNA><RNA Gene Products><Regulatory T-Lymphocyte><Research><Rheumatoid Arthritis><Ribonucleic Acid><Role><S100A8><S100A8 gene><SIS cytokines><Scientist><Shapes><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Interfering RNA><Sodium Dextran Sulfate><Sorting><Specificity><Surface><System><T-Cell Activation><T-Cell Development><T-Cell Ontogeny><T-Lymphocyte Development><TP53><TP53 gene><TRP53><Therapeutic><Therapeutic Agents><Tissue Growth><Tissues><Toronja><Treg><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><Turmeric Yellow><Veiled Cells><Vesicle><Veterans><Vitamin M><Work><Zingiber officinale><activate T cells><adipose><adiposity><aged><alcohol prevention><anergy><anti-cancer research><anti-inflammatory effect><anti-microbial><antimicrobial><bacteria in the gut><balance><balance function><biological signal transduction><bowel><broccoli sprout><c myc><c-myc Genes><cancer in the colon><cancer prevention><cancer progression><cancer research><career><cell type><cellular differentiation><chemoattractant cytokine><chemokine><chemokine receptor><chronic disorder><cmyc><cognitive dysfunction><cognitive loss><colitis mouse model><colitis murine model><colitis-induced dysbiosis><colon neoplasia><corpulence><cytokine><dectin 1><developmental><dextran sulfate sodium colitis><dextran sulfate sodium induced colitis><dextran sulfate sodium model><dextran sulfate sodium mouse model><diabetes><diets><digestive tract microbiome><disease diagnosis><drug/agent><enteric microbial community><enteric microbiome><enteric microbiota><exosome><expression vector><gastrointestinal microbial flora><gastrointestinal microbiome><genetic promoter element><genetic promoter sequence><gitter cell><gut bacteria><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><health care><health level><hepatic body system><hepatic inflammation><hepatic organ system><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive myeloid cells><immunosuppressive response><improved><in vivo><inflamed joint><inflamed liver><insight><insulin resistant><insulin tolerance><interleukin-22><interspecies communication><interspecies cross-talk><interspecies signaling><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><intraoral drug delivery><joint damage><joint inflammation><joint injury><joint swelling><joint trauma><lipid based nanoparticle><lipid nanoparticle><liver inflammation><malignancy><member><mesoglia><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><microglial cell><microgliocyte><military veteran><mouse colitis><mouse model><murine colitis><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><nano particle><nano vector><nano-sized particle><nanoparticle><nanosized particle><nanovector><natural killer cell based immunotherapy><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ob/ob mouse><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><patient population><perivascular glial cell><post-trauma stress disorder><posttrauma stress disorder><pressure><prevent><prevent alcohol><preventing><preventing alcohol><promoter sequence><protein p53><recruit><regulatory T-cells><rheumatic arthritis><siRNA><side effect><site targeted delivery><small molecule><social role><stem cells><suppressive myeloid cells><targeted delivery><theranostics><therapeutic agent development><therapeutic development><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><tissue repair><translational study><traumatic neurosis><treatment strategy><tumor><tumor progression><tumor suppressor><tumors in the brain><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><veteran population><vitamin Bc><white adipose tissue><yellow adipose tissue>