ER chaperones and perinatal growth in Prader-Willi syndrome: therapy and mechanisms

Summary

With a newly established mouse model of PWS that remarkably models the unique pattern of nutritional phases in PWS development, Dr. Nicholls will measure gene expression, hormones, and metabolites to understand these phases, the triggers for transitions between them, and the ideal time for a treatment to improve production of multiple hormones.

Lay Abstract

Each person with Prader-Willi syndrome (PWS) requires lifelong medical care, beginning in newborns and infancy with difficulty feeding and lack of interest in food transitioning in childhood to an obsessive focus on food and insatiable feeding (“hyperphagia”). Other clinical issues include cognitive and behavioral impairment, hormone abnormalities, and scoliosis. Rather than a simple two step transition in food-related behaviors, recent studies defined seven nutritional growth phases in PWS that highlight clinical complexity. While GH therapy treats short stature and improves muscle function, it does not alter nutritional phases and progression from disinterest in food to hyperphagia. There are no effective treatments for nutritional, metabolic or behavioral abnormalities in PWS, and to date, no model system has accurately modeled these aspects of PWS across early life stages. Under year 1 of FPWR funding to investigate a PWS mouse model with early neonatal lethality due to very low levels of blood sugar – critically required for brain function and development – and that we have previously associated with defects in pancreatic hormone cells (ß-cells) producing insulin that controls blood sugar, we have established a new mouse model of PWS that remarkably models the unique pattern of growth phases in PWS across perinatal development.

We established a new animal model by breeding from the standard inbred to a more genetically diverse outbred background, typical litters having ~14 pups half that are PWS and half wildtype (WT), with removal after 1-3 days of all WT but one to allow better postnatal survival of PWS. Amazingly, we found five clear nutritional growth phases of PWS mice, with 1) mild growth retardation before birth, 2) slow but steady growth during week 1 after birth, 3) a remarkable phase with no growth at all for 7-9 days in week 2 that corresponds to the human neonatal-juvenile phase, followed by 4) a rapid catch-up growth phase to weaning, and 5) a subsequent slow but variable growth phase on transition from fat-rich milk to carbohydrate-rich chow. These unique PWS perinatal growth phases for the first time provide an opportunity to understand the pathophysiological basis of PWS across all body systems. For this competing renewal, we will expand this new mouse model resource and continue prior work to assess small molecule therapeutics in ß-cells and for PWS postnatal phenotypes. New aims include assessment of key hormones involved in early postnatal growth, and integration of data from unbiased screens for abnormal metabolites and RNA expression in key tissues, focusing initially on growth phase 3, to identify those dysregulated in PWS. These studies will show that PWS-imprinted genes are critical for neonatal-to-perinatal and juvenile transitions in adaptation to life after birth. The study will illuminate metabolic, hormonal, and gene regulatory pathways underlying nutritional phases in PWS, identify new biomarkers for PWS, and expand preclinical therapeutic application and assessment.