PROJECT DESCRIPTION One in six pregnancies is affected by some form of gestational diabetes (GD), a prevalence that is steadily rising in the context of the worldwide epidemics of obesity and early diabetic onset. Early diagnosis and advances in maternal glucose control have greatly mitigated the perinatal consequences of gestational diabetes on the mothers and their offspring. However, these advances have only marginally impacted its long-term consequences. As such, exposure to hyperglycemia in utero remains associated with increased long-term morbidities in offspring. The mechanisms driving this pathological transmission across generations have not been established. The overarching hypothesis of this project is that the hematopoietic stem cells (HSCs) of the offspring are stably altered by gestational diabetes and are essential “effectors” of the long-term pathological effects of gestational diabetes in offspring. Our preliminary data established two reliable mouse models of gestational diabetes that reproduce not only the perinatal adverse features of the human pathology, but also its long-term consequence in adult offspring. In these models, we show that gestational diabetes alters the hematopoiesis of the offspring and that this effect persists to adulthood, even in absence of overt diabetes. This phenotype indicates the acquisition of a long-lasting memory of metabolic events by the most upstream hematopoietic stem cell (HSC) compartments. Importantly, our results also indicate that hematopoietic alterations present in offspring can contribute to pathologies, such as atherosclerosis. Here we propose to investigate the interplay between gestational diabetes and the hematopoietic system. Based on our preliminary data, we will determine in aim 1 how signaling through the receptor of advanced glycation end products (RAGE) contributes to the acquisition of a diabetic hematopoietic memory in GD offspring. In aim 2, we will establish the epigenetic modifications that underlie the long-term maintenance of this hematopoietic memory in adult GD offspring. Our work will decipher the mechanisms underlying the hematopoietic memory associated with gestational diabetes. Defining these mechanisms will establish potential biomarkers for diabetic hematopoietic memory. it will also reveal new therapeutic targets to alter the trajectory of the hematopoietic memory and prevent its long-term pathological consequences.