Project Grant F32AG094179

DNA NANOTECHNOLOGY AS A TOOL TO ADVANCE UNDERSTANDING OF NEURODEGENERATIVE DISEASE - PROJECT SUMMARY DISEASES RELATING TO NEURODEGENERATION ARE INCREASINGLY WIDESPREAD, AFFECTING MILLIONS OF PEOPLE EVERY YEAR, AND YET ARE DIFFICULT TO DIAGNOSE BECAUSE OF THE CHALLENGES ASSOCIATED WITH BOTH THE IDENTIFICATION AND QUANTIFICATION OF BIOMARKERS. PATIENTS WITH NEURODEGENERATIVE DISEASES LIKE ALZHEIMER'S DISEASE (AD) OR PARKINSON'S DISEASE (PD) HAVE A LONG ASYMPTOMATIC PRECLINICAL PHASE AND THE DISEASES ARE NOT TYPICALLY DIAGNOSED UNTIL SYMPTOMS START, WHEN SIGNIFICANT NEURONAL DEGENERATION HAS ALREADY OCCURRED. DECADES OF DRUG DEVELOPMENT AIMED AT REMOVING THE AMYLOID PLAQUES OBSERVED IN ALZHEIMER'S DISEASE HAVE ONLY YIELDED THREE FDA-APPROVED DRUGS TO DATE, ONE WITH CONTENTIOUS EFFICACY. THESE PLAQUES ARE THE RESULT OF THE ABERRANT AGGREGATION OF THE PEPTIDE AMYLOID B (AB). ALTHOUGH THERAPEUTIC STRATEGIES TARGETING MISFOLDED PROTEINS SUCH AS AB HAVE EXPERIENCED SIGNIFICANT ATTRITION, SUPPORT FOR THIS APPROACH HAS COME FROM THE RECENT APPROVAL OF THE ANTIBODIES DONANEMAB, LECANEMAB AND ADUCANUMAB BY THE FDA FOR THE TREATMENT OF AD. THESE ADVANCES, HOWEVER, SHOULD NOT HIDE THE FACT THAT AD IS A MULTIFACTORIAL DISORDER CHARACTERIZED NOT JUST BY AB AND TAU PROTEIN AGGREGATION, BUT ALSO BY EXCITOTOXICITY, SYNAPTIC LOSS, INFLAMMATION, CHOLINERGIC DYSFUNCTION, OXIDATIVE STRESS, GLUCOSE HYPOMETABOLISM, ALTERATIONS TO THE GUT MICROBIOME, THE IMMUNE PATHWAY, THE ENDOCRINE PATHWAY, AND BACTERIA-DERIVED METABOLITES. OUR APPROACHES WILL AID IN UNTANGLING THE CONTRIBUTIONS OF THESE FACTORS THROUGH BIOMARKER DETECTION. IN THE MOLECULAR SYSTEMS LAB, WE DEVELOP TOOLS BASED ON DNA NANOTECHNOLOGY WHICH INVESTIGATE EARLY STAGES OF DISEASE PROGRESSION AND THE MECHANISMS OF DISEASE. OUR DNA BASED TECHNOLOGIES CAN DETECT SUB-FEMTOMOLAR QUANTITIES OF PROTEIN BIOMARKERS FROM LOW SAMPLE VOLUMES AND HAS THE HAS POTENTIAL TO DETECT AD AND PD BIOMARKERS (AB-42, NEUROFILAMENT LIGHT CHAIN, P-TAU, P-A-SYNUCLEIN). ANOTHER ADVANTAGE IS THE POTENTIAL TO CHARACTERIZE ABERRANTLY AGGREGATED OLIGOMERIC PROTEINS, AN ESSENTIAL BIOMARKER FOR TRACKING DISEASE PROGRESSION, WHICH IS DIFFICULT TO CHARACTERIZE USING THE CURRENT STATE OF THE ART. UNDERSTANDING THE DISEASE PROCESSES BEHIND BIOMARKER PRODUCTION AND QUANTIFYING THE LEVEL OF THESE BIOMARKERS IS ESSENTIAL TO BOTH UNDERSTANDING THE DISEASE AND TO SAVING THE LIVES OF THOSE EFFECTED BY THE DISEASE.