Project Grant R01HD110408

TARGETING PROTEINOPATHY/TAUOPATHY AND IMPAIRED AUTOPHAGY FOR MECHANISTIC UNDERSTANDING AND THERAPEUTIC INTERVENTION OF PREECLAMPSIA - SUMMARY PREECLAMPSIA (PE) IS A LEADING CAUSE OF MATERNAL AND FETAL MORBIDITY AND MORTALITY AND COMPLICATES 3-8% OF ALL PREGNANCIES. THIS PREGNANCY COMPLICATION IS DEFINED BY DE NOVO HYPERTENSION ARISING AFTER 20 WEEKS OF GESTATION AND NEAR TERM WITH PROTEINURIA OR OTHER SIGNS OF END-ORGAN DAMAGE. PE HAS BEEN LINKED TO HIGH INCIDENCE OF CHRONIC DISEASES LATER IN LIFE, INCLUDING CARDIOVASCULAR DISEASE, DIABETES MELLITUS, AND RENAL DISEASE. THUS, DIRECTED THERAPY IS CRITICALLY IMPORTANT TO IMPROVE BOTH MATERNAL AND NEONATAL OUTCOMES. HOWEVER, TO DATE, NO EFFECTIVE THERAPY FOR THIS SYNDROME IS CLINICALLY AVAILABLE. THE MOST EFFECTIVE TREATMENT IS DELIVERY OF THE PLACENTA. OUR RECENT NOVEL FINDINGS SUGGEST THAT PE AND ALZHEIMER'S DISEASE (AD) SHARE A COMMON ETIOLOGY OF PROTEINOPATHY AND IMPAIRED AUTOPHAGY AND THAT ACCUMULATION OF PROTEIN AGGREGATES IN THE PE PLACENTA DIRECTLY RESULTS FROM DYSREGULATED LYSOSOMAL BIOGENESIS. OUR WORK ALSO SUGGESTS THAT IMPAIRED AUTOPHAGY NOT ONLY ENHANCE PROTEIN AGGREGATE ACCUMULATION BUT ALSO INDUCES STERILE INFLAMMATION AND REDUCES ENDOVASCULAR ABILITY OF TROPHOBLASTS. THIS WORK HAS LED TO SEARCH FOR THERAPEUTIC INTERVENTIONS THAT UNIQUELY TARGET IMPAIRED AUTOPHAGY AND TOXIC PROTEIN AGGREGATION. OUR PRELIMINARY RESULTS SUGGEST THAT A NON- MAMMALIAN DISACCHARIDE, TREHALOSE AND ITS LACTO ANALOG LACTOTREHALOSE, RESTORED AUTOPHAGY AND INHIBITED PROTEIN AGGREGATION IN A HUMANIZED MOUSE MODEL OF PE AS WELL AS IN HYPOXIA-EXPOSED PRIMARY HUMAN TROPHOBLASTS. IN THE MOUSE MODEL, TREHALOSE COULD BE EFFECTIVE IN BOTH PREVENTION AND TREATMENT SETTINGS. WE PROPOSE TO EXPAND ON THESE INTRIGUING PRELIMINARY RESULTS AND PROPOSE NOVEL EXPERIMENTS TO ASSESS THE EFFICACY OF TREHALOSE AND LACTOTREHALOSE FOR TREATMENT OF PE. MOREOVER, WE PLAN TO EXAMINE WHETHER TREHALOSE AND LACTOTREHALOSE CAN REVERSE TRANSCRIPTOME-WIDE CHANGES AND INFLAMMATION ASSOCIATED WITH PE IN IN VIVO AND IN VITRO MODELS. THE SPECIFIC AIMS PROPOSED IN THIS PROPOSAL ADHERE TO THE OVERARCHING GOAL OF ESTABLISHING PRE-CLINICAL AND CELLULAR MODELS TO ASSESS THEIR SIGNIFICANCE IN REVERSING PE-ASSOCIATED PATHOLOGICAL PATHWAYS. BASED ON MECHANISTIC INSIGHTS INTO THE PATHOGENESIS OF PE, OUR PROPOSED RESEARCH WILL ASSESS THE ABILITY OF A SMALL, INEXPENSIVE, AND NON-MAMMALIAN DISACCHARIDE TO PREVENT AND TREAT PE. THIS STRAIGHT FORWARD INTERVENTION AND REVERSAL OF PE PATHOLOGY IN WELL-DEFINED PRE-CLINICAL AND CELLULAR MODELS MAY PROVIDE A BASIS FOR CLINICAL EVALUATION OF TREHALOSE AND LACTOTREHALOSE IN PREGNANT WOMEN.