Project Grant R21HD116039

INTER-GENERATIONAL CARDIOMETABOLIC RISK: EXPLORE UNDERLYING IMMUNE PATHWAYS - ABSTRACT DESPITE DECADES OF CONCERTED EFFORTS, THE PREVALENCE OF OBESITY AND ITS ASSOCIATED MORBIDITIES SUCH AS TYPE 2 DIABETES (T2D) AND CARDIOVASCULAR DISEASES (CVD) CONTINUE TO CLIMB IN THE US AND RACIAL AND ETHNIC MINORITY POPULATIONS LIVING IN LOW-INCOME HOUSEHOLDS AND COMMUNITIES ARE DISPROPORTIONALLY AFFECTED. PART OF THE REASON IS A WELL-OBSERVED VICIOUS CYCLE OF INTERGENERATIONAL AMPLIFICATION. HOWEVER, THE UNDERLYING PATHWAYS DRIVING THIS CYCLE REMAIN POORLY UNDERSTOOD. THIS PROPOSAL AIMS TO EXPLORE A NOVEL HYPOTHESIS REGARDING THE ROLE OF CLINICAL AND SUBCLINICAL INFECTION AND RESULTING INFLAMMATION IN THE INTERGENERATIONAL CARDIOMETABOLIC LINK. THE PROPOSED STUDY IS MOTIVATED BY A STRONG SCIENTIFIC PREMISE. FIRST, GROWING EVIDENCE GENERATED BY US AND OTHERS DEMONSTRATED THAT MATERNAL CARDIOMETABOLIC CONDITIONS CONTRIBUTE TO CHILD CARDIOMETABOLIC RISKS. THIS INTERGENERATIONAL LINK MAY ORIGINATE IN UTERO AND AMPLIFY THE CARDIOMETABOLIC RISK IN CURRENT AND FUTURE GENERATIONS, UNDERSCORING THE IMPORTANCE OF THE EARLY LIFE PERIOD. SECOND, THERE IS GROWING EVIDENCE THAT INFECTION MAY LEAD TO BOTH A LOCAL AND SYSTEMIC INFLAMMATORY STATE. IN THE CONTEXT OF MATERNAL- FETAL DYAD, MATERNAL INFECTION WAS FOUND TO BE ASSOCIATED WITH INCREASED LEVELS OF PRO- AND ANTI-INFLAMMATORY CYTOKINE LEVELS IN CORD BLOOD, INDEPENDENT OF VERTICAL PATHOGEN TRANSMISSION. TO DATE, LITTLE IS KNOWN ABOUT METABOLIC-IMMUNE SYSTEM CROSSTALK IN EARLY LIFE AND HEALTH IMPLICATIONS. THE OVERARCHING GOAL OF THIS PROJECT IS TO INVESTIGATE THE ASSOCIATION OF THE EARLY LIFE ANTIBODY PROFILE TO A BROAD ARRAY OF PATHOGENIC AND COMMENSAL MICROBES AND SYSTEMIC IMMUNOPROTEOMIC PROFILES IN THE INTERGENERATIONAL CARDIOMETABOLIC LINK. WE WILL ALSO EXPLORE MICRONUTRIENT STATUS AS A PROTECTIVE FACTOR. SPECIFICALLY, WE AIM TO 1) IDENTIFY EARLY LIFE IMMUNE RESPONSE SIGNATURES OF LONG-TERM CARDIOMETABOLIC OUTCOMES; 2) EXAMINE THE ROLE OF EARLY LIFE IMMUNE RESPONSES IN THE INTERGENERATIONAL CARDIOMETABOLIC LINK; AND 3) EXPLORE THE INTERPLAY OF EARLY LIFE MICRONUTRIENT STATUS AND IMMUNE RESPONSES ON THE INTERGENERATIONAL LINK OF CARDIOMETABOLIC OUTCOMES. WE WILL LEVERAGE THE RICH RESOURCES OF THE BOSTON BIRTH COHORT (BBC), WITH ~3,500 MOTHER-CHILD PAIRS WHO WERE ENROLLED AT BIRTH AND FOLLOWED PROSPECTIVELY. WE HAVE SHOWN THAT THE BBC IS A HIGH-RISK POPULATION FOR ADVERSE CARDIOMETABOLIC OUTCOMES. A PARTICULARLY NOVEL ASPECT OF THIS STUDY IS THAT WE WILL LEVERAGE EXISTING ANTIBODY REPERTOIRE DATA GENERATED BY CUTTING-EDGE TECHNOLOGY (PHIP-SEQ) AND IMMUNOPROTEOMIC PROFILES GENERATED BY THE HIGH- THROUGHPUT OLINK PLATFORM AT TWO CRITICAL DEVELOPMENTAL WINDOWS: AT BIRTH (REFLECTING THE IN-UTERO STATE) AND AT AGE 1-2 YEARS (REFLECTING EARLY LIFE IMMUNE RESPONSE). SUCCESSFUL COMPLETION OF THIS STUDY WILL HELP TO DEEPEN OUR UNDERSTANDING OF THE IMMUNOLOGIC PATHWAYS UNDERLYING THE INTERGENERATIONAL CARDIOMETABOLIC LINK, REVEAL NOVEL BIOMARKERS AND TARGETS, AND LEAD TO A NEW PARADIGM FOR EARLY PREDICTION AND PREVENTION TO HALT OR REVERSE THE VICIOUS INTERGENERATIONAL CYCLE OF CARDIOMETABOLIC DISEASE.