PREECLAMPSIA (PE) IS A LATE PREGNANCY DISORDER, AFFECTING ~8% OF FIRST-TIME PREGNANCIES CHARACTERIZED BY HYPERTENSION, PROTEINURIA AND MATERNAL VASCULAR DAMAGE THAT CAN CAUSE LIFE-THREATENING COMPLICATIONS FOR BOTH MOTHER AND CHILD AND LONG TERM MORBIDITY. SPECIALLY SEVERE PREECLAMPSIA (SPE) IS DIAGNOSED BASED ON A FURTHER ELEVATION OF BLOOD PRESSURE, HELLP SYNDROME AND/ OR ECLAMPSIA. CURRENTLY, THE ONLY DEFINITIVE CURE IS DELIVERY OF THE PLACENTA, AND THEREFORE THE INFANT REGARDLESS OF ITS GESTATIONAL AGE, CONTRIBUTING TO PREMATURE DELIVERY. AS A RESULT, PE ACCOUNTS FOR MORE THAN 76,000 MATERNAL AND 500,000 INFANT DEATHS WORLDWIDE EACH YEAR AND IMPORTANT PUBLIC HEALTH EXPENDITURES ASSOCIATED WITH MATERNAL AND NEONATAL MORBIDITY AND 25-30% INCREASED RISK OF DEVELOPING CARDIOVASCULAR DISEASES LATER IN LIFE._x000D_ ALTHOUGH THIS DISORDER IS A PUBLIC HEALTH PROBLEM, ITS PATHOGENESIS IS NOT YET WELL UNDERSTOOD. IT IS WIDELY ACCEPTED THAT THE PLACENTA PLAYS A CENTRAL ROLE, WITH DEFICIENT CYTOTROPHOBLAST (CTB) INVASION OF UTERINE SPIRAL ARTERIOLES BEING A CAUSAL FACTOR. CURRENTLY, THE PATHOGENESIS OF PE IS CONCEPTUALIZED IN A TWO-STAGE MODEL WITH THE PLACENTAL DEFECT PRECIPITATING AN ABNORMAL VASCULAR MATERNAL RESPONSE THAT MANIFESTS AS THE SIGNS OF THIS PATHOLOGICAL CONDITION. HOWEVER, DESPITE AN APPARENTLY IN-DEPTH UNDERSTANDING OF THE PATHOPHYSIOLOGY OF PE, WE HAVE NOT BEEN ABLE TO RELIABLY PREDICT OR PREVENT THIS DISEASE. THEREFORE, NEW APPROACHES TO DIAGNOSE, PREVENT AND TREAT PE FROM A DIFFERENT PERSPECTIVE ARE URGENTLY NEEDED. THE NOVELTY OF THIS PROPOSAL FOCUSES ON A NEW RESEARCH PERSPECTIVE BASED ON THE MATERNAL CONTRIBUTION TO THE PATHOGENESIS OF LATE PREGNANCIES DISORDERS WITH PARTICULAR ATTENTION TO PE. BASED ON OUR PUBLISHED WORK AND UNPUBLISHED DATA, THE FOCUS OF THIS PROPOSAL TAKES A STEP FORWARD IN SUGGESTING THAT ENDOMETRIAL DECIDUALIZATION RESISTANCE (DR) IN THE MATERNAL UTERUS AS A CAUSATIVE FACTOR FOR PE._x000D_ SINCE DR IS A DISORDER THAT MIGHT BE ENCODED IN THE GENOME/EPIGENOME OR EXPRESSED IN THE TRANSCRIPTOME, WE AIM: I) TO IDENTIFY THE TRANSCRIPTOMIC/GENETIC/EPIGENETIC CAUSES RESPONSIBLE FOR THE EMERGENCE OF ENDOMETRIAL DR IN SPE PATIENTS; II) TO IDENTIFY THE MOLECULAR MECHANISMS LINKING DR IN SPE WITH IMPAIRED CYTOTROPHOBLAST INVASION IN VITRO, AND III) TO GENERATE A DR PHENOTYPE ANIMAL MODEL USING GENE EDITING TECHNOLOGIES IN ORDER TO INVESTIGATE AND/OR DEVELOP POSSIBLE THERAPEUTIC STRATEGIES TO RESTORE A NORMAL DECIDUAL PHENOTYPE PRIOR TO PREGNANCY. _x000D_ THIS PROJECT OPENS A NEW DIRECTION FOR RESEARCH INTO THE MATERNAL CAUSES OF SPE THAT MAY LEAD TO THE DEVELOPMENT OF CLINICALLY USEFUL TESTS TO ENABLE PROSPECTIVE RISK EVALUATION AND POSSIBLE TREATMENT OF THIS MAJOR PUBLIC HEALTH PROBLEM.