R01DK144500

ENGINEERED METABOLITE-BASED NANOPARTICLES FOR IMMUNOMODULATION OF MACROPHAGES TO TREAT OBESITY - PROJECT SUMMARY OBESITY CAN BE CHARACTERIZED AS A MULTIFACTORIAL PATHOLOGY AND A CHRONIC LOW-GRADE INFLAMMATORY DISEASE THAT IS ACCOMPANIED BY METABOLIC DYSREGULATION. MORE THAN TWO BILLION PEOPLE WORLDWIDE ARE OBESE, WITH APPROXIMATELY 167 MILLION NEW ADULTS AND CHILDREN BECOMING OVERWEIGHT OR OBESE BY THE END OF 2025. OBESITY IS OF CRITICAL CONCERN DUE TO ITS WIDE-REACHING ASSOCIATIONS WITH METABOLIC DISEASES, INCLUDING NON-ALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASE, AND TYPE II DIABETES. CURRENT OBESITY TREATMENTS CAN BE BROADLY CATEGORIZED INTO LIFESTYLE MODIFICATIONS AND MEDICAL INTERVENTIONS, INCLUDING SURGERY AND PHARMACOTHERAPY. DESPITE THE RECENT SUCCESS OF ANTI-OBESITY MEDICATIONS, THEY STILL SUFFER FROM LIMITATIONS, INCLUDING FREQUENT DOSING REQUIREMENTS, HIGH COST (E.G., GLP-1 AGONISTS), NON-RESPONDER ISSUES, AND POTENTIAL FOR SERIOUS SIDE EFFECTS. SEVERAL STUDIES HAVE SUGGESTED THAT AN IMBALANCE IN THE RATIO OF M2-TO-M1 MACROPHAGES IN ADIPOSE TISSUE IS ASSOCIATED WITH OBESITY, WHERE NEWLY RECRUITED MACROPHAGES TEND TO ADOPT A “PRO-INFLAMMATORY” M1-LIKE PHENOTYPE COMPARED TO TISSUE-RESIDENT MACROPHAGES THAT TEND TO HAVE AN “ANTI-INFLAMMATORY” M2-LIKE PHENOTYPE. OUR LONG-TERM GOAL IS TO DEVELOP A SIMPLE AND BROAD-ACTING NANOPARTICLE (NP)-BASED IMMUNOTHERAPY TO ACHIEVE SUSTAINED IMPROVEMENTS IN LOCAL AND SYSTEMIC INFLAMMATION, RESTORE THE M2/M1 BALANCE IN ADIPOSE TISSUE, RESTORE METABOLIC HEALTH, AND LIMIT COMORBIDITY DEVELOPMENT IN OBESE PATIENTS. NPS OFFER AN EFFECTIVE STRATEGY TO MODULATE MACROPHAGE POLARIZATION THROUGH THE DELIVERY OF BIOACTIVE SUBSTANCES, BALANCING THE LOW-GRADE INFLAMMATORY RESPONSE, WHILE ENABLING LOCAL RETENTION AND CONTROLLED RELEASE PROPERTIES. HOWEVER, EFFECTIVE DELIVERY WITH NPS OFTEN REQUIRES HIGH DOSES AND FREQUENT ADMINISTRATION DUE TO LOADING/ENCAPSULATION/DRUG RETENTION ISSUES. THROUGH AN INNOVATIVE APPROACH, OUR LAB HAS DEVELOPED IMPRINT-NPS (IMMUNOMODULATORY PARTICLES FOR REVERSING INFLAMMATION AND PHENOTYPE TRANSFORMATION) PREPARED FROM BIODEGRADABLE POLYESTERS SYNTHESIZED FROM ENDOGENOUSLY PRODUCED BIOACTIVE METABOLITES. COMPARED TO TRADITIONAL NP APPROACHES, IMPRINT-NPS ARE UNIQUE AS THEY ARE ‘DRUG-FREE’ AND THEIR ACTIVITY DEPENDS ON THEIR COMPOSITION RATHER THAN ENCAPSULATED AGENTS. OUR STRONG PRELIMINARY DATA SHOWED THAT METABOLITE-BASED POLYMERIC NPS COULD INDUCE POTENT ANTI-INFLAMMATORY RESPONSES, REPOLARIZE M1-TO-M2 PHENOTYPES, INDUCE FAT BROWNING, AND ENHANCE SENSITIVITY WHILE REDUCING WEIGHT GAIN IN A HIGH-FAT DIET (HFD)-INDUCED OBESITY MOUSE MODEL. HEREIN, WE PROPOSE TO EVALUATE THE IMMUNOMODULATORY RESPONSES OF METABOLITE-BASED POLYMERS AND IMPRINT-NPS FOR THE MODULATION OF MACROPHAGES AND ADIPOCYTES, FOCUSING ON STRUCTURE-FUNCTION RELATIONSHIPS AND MECHANISTIC INVESTIGATIONS (AIM 1). NEXT, IN AIM 2, WE WILL EXAMINE THE IN VIVO TOXICITY, ABILITY OF IMPRINT-NPS TO MODULATE LOCAL AND SYSTEMIC RESPONSES, MACROPHAGE POLARIZATION, ADIPOSE TISSUE FUNCTION, AND OBESITY OUTCOMES. THE DOSING AND TIMING EFFECTS OF IMPRINT-NPS WILL BE OPTIMIZED AND MECHANISTICALLY EVALUATED. FINALLY, THEIR EFFICACY WILL BE EXPLORED IN COMBINATION WITH A CLINICALLY RELEVANT GLP-1 RECEPTOR AGONIST TO ASSESS POTENTIAL EFFICACY ENHANCEMENTS.

Terasaki Institute For Biomedical Innovation

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

California United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)