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CAREER: ENGINEERING THE NANOPARTICLE INTERFACE FOR TUNABLE BIOMOLECULAR AGGREGATION -NON-TECHNICAL SUMMARY WHEN YOU HAVE A HEADACHE OR OTHER MINOR ACHES OR PAIN, YOU TAKE A PILL TO FEEL BETTER. ONCE SWALLOWED, THE PILL MAKES ITS WAY TO YOUR STOMACH AND RELEASES AN ACTIVE DRUG, WHERE IT CAN ENTER YOUR BLOODSTREAM AND BEGIN TO LESSEN YOUR ACHES AND PAINS. ONE SIMPLE DRUG CAN TREAT NUMEROUS DIFFERENT ACHES AND PAINS, REGARDLESS OF THE SPECIFIC CAUSE OF THE PAIN. THE ABILITY TO TREAT MANY DIFFERENT CONDITIONS HAS ADVANTAGES, BUT IT ALSO RESULTS IN A LONG LIST OF POTENTIAL SIDE EFFECTS. SOME OF THESE SIDE-EFFECTS COULD BE AVOIDED IF THE DRUG WOULD SPECIFICALLY TARGET THE SOURCE OF THE CONDITION, AND NOT ACCUMULATE IN OTHER PARTS OF THE BODY. NANOMETER-SCALE MATERIALS, SUCH AS NANOPARTICLES, CAN PREVENT DRUG ACCUMULATION IN HEALTHY TISSUES, THEREBY LIMITING SIDE EFFECTS. THE PROBLEM IS THAT THE USE OF NANOPARTICLES TO TREAT A MYRIAD OF DISEASES THAT IMPACT NATIONAL HEALTH IS CURRENTLY HAMPERED BY YOUR OWN IMMUNE SYSTEM. YOUR IMMUNE SYSTEM RECOGNIZES NANOPARTICLES AS A FOREIGN BODY BY USING CERTAIN IMMUNE RECOGNITION PROTEINS PRESENT IN THE BLOOD. NOT ALL PROTEINS PRESENT IN BLOOD PARTICIPATE IN IMMUNE RECOGNITION, AND THE SELECTIVE ACCUMULATION OF THESE ?GOOD? PROTEINS CAN POTENTIALLY AID IN EVADING IMMUNE CELLS. THIS PROJECT PROBES THE WAY IN WHICH SUGAR MOLECULES THAT NATURALLY OCCUR IN OUR BODIES CAN BE USED TO SELECTIVELY ACCUMULATE PROTEINS ON THE NANOPARTICLE SURFACE. THE SELECTIVE BUILDING OF PROTEIN LAYERS ON THE SUGAR-DECORATED NANOPARTICLES WILL SERVE TO EVADE IMMUNE RECOGNITION, AS WELL AS SERVE AS A DRUG-FREE MATERIAL CAPABLE OF REMOVING PROTEINS THAT ARE INVOLVED IN PAIN. INTEGRATION OF EDUCATIONAL ACTIVITIES WITH THIS RESEARCH PROGRAM ARE DESIGN TO INCREASE RECRUITMENT AND RETENTION OF WOMEN AND UNDER-REPRESENTED GROUPS IN NANOTECHNOLOGY CAREERS. EDUCATIONAL ACTIVITIES INCLUDE WORKSHOPS FOR HIGH SCHOOL STUDENTS TO SHOWCASE THE SCIENCE BEHIND NANOMATERIALS USED IN OUR DAILY LIVES, DEVELOPMENT OF INSTRUCTIONAL PROGRAMS AND VIDEOS FOR MIDDLE SCHOOL STUDENTS, AND PEER MENTORSHIP PROGRAMS. TECHNICAL SUMMARY THIS PROPOSAL AIMS TO ENGINEER POLYMERIC NANOPARTICLES (NPS) THAT GOVERN CYTOKINE BIOAVAILABILITY THROUGH MANIPULATION OF THE INTERFACIAL BEHAVIOR OF THE NP WITHIN BIOLOGICAL SYSTEMS. CYTOKINES INSTRUCT CELLS, BUT ABERRANT CYTOKINE PRESENCE EXACERBATES DISEASE PROGRESSION. EXISTING STRATEGIES TO MITIGATE UNWANTED CYTOKINES RELY ON ACTIVE DRUGS TO TARGET PATHWAYS UPSTREAM OF THESE CYTOKINES. ACTIVE DRUGS CAN ACCUMULATE IN OFF-TARGET TISSUES OR MAY HAVE BROAD-ACTING EFFECTS RESULTING IN FURTHER COMPLICATIONS, HIGHLIGHTING THE NEED FOR NOVEL STRATEGIES TO GOVERN CYTOKINE BIOAVAILABILITY IN THE INFLAMMATORY MILIEU. NPS CAN BE USED TO DELIVER ACTIVE DRUGS, RESULTING IN FEWER OFF-TARGET COMPLICATIONS COMPARED TO THE DRUG ALONE. EVEN STILL, NPS ARE REMOVED BY FILTERING ORGANS AND IMMUNE CELLS IN RESPONSE TO THE AGGREGATION OF SERA PROTEINS ON THE NP SURFACE THAT COMPRISE THE BIOMOLECULAR CORONA. WHILE FORMATION OF THE BIOMOLECULAR CORONA IS A KNOWN ROADBLOCK IN NP DESIGN FOR THERAPEUTIC TREATMENT, THIS PROPOSAL WILL ESTABLISH A NEW SET OF BIOCHEMICAL TOOLS TO LEVERAGE THE BIOMOLECULAR CORONA AS A THERAPEUTIC AGENT BY USING SULFATED POLYSACCHARIDES WITH STRONG BINDING AFFINITY FOR INFLAMMATORY CYTOKINES TO SELECTIVELY FORM THE NP BIOMOLECULAR CORONA. TO DO SO, THREE SPECIFIC THRUSTS WILL BE EXPLORED: 1) DEPLOY SULFATED POLYSACCHARIDES TO SELECTIVELY BUILD THE BIOMOLECULAR CORONA BY OUTCOMPETING SERA PROTEIN AGGREGATION ON NPS, 2) ENGINEER BIOMOLECULAR CORONA FORMATION TO SELECTIVELY SEQUESTER INFLAMMATORY CYTOKINES, AND 3) INDUCE CELLULAR UPTAKE VIA PHAGOCYTOSIS OF NPS ADORNED WITH TAILORED BIOMOLECULAR CORONAS TO PERMANENTLY REMOVE INFLAMMATORY CYTOKINES BOUND TO THE NPS. THE PROPOSED RESEARCH WILL IDENTIFY HOW POLYSACCHARIDE SULFATION PATTERNS CONTROL BIOMOLECULAR CORONA FORMATION AND PHAGOCYTOSIS OF NANOMATERIALS, WITH POTENTIAL APPLICATIONS IN ENGINEERING NOVEL NANOMEDICINE APPROACHES FOR TREATMENT OF SEVERAL DISEASES. INTEGRATION OF THESE FOUNDATIONAL STUDIES WITH EDUCATIONAL ACTIVITIES WILL PROVIDE IN-DEPTH EXPOSURE TO THE FIELD OF NANOTECHNOLOGY, AS WELL AS PEER MENTORING TO ENABLE RECRUITMENT AND RETENTION OF WOMEN AND STUDENTS FROM UNDER-REPRESENTED GROUPS IN THE GROWING FIELD OF NANOTECHNOLOGY THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.
$133.0k 1/4/24