Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR) and contributes to both perinatal and long term morbidity because it effects both neonatal and adult metabolism. As adults, IUGR individuals are prone to dyslipidemia and insulin resistance. Fatty acid metabolism and insulin stimulated glucose uptake are key components of skeletal muscle metabolism. Inappropriately increased skeletal muscle fatty acid oxidation relative to glucose oxidation is associated with insulin resistance, and this association raises the possibility that altered adult mitochondrial metabolism is initiated in the fetus by the IUGR intrauterine milieu. Preliminary data from our lab demonstrates that mitochondrial function and L-3-hydroxyacyl CoA dehydrogenase gene expression (L3HD) are effected in rats who are IUGR secondary to placental insufficiency. We therefore hypothesize that increased gene expression and function of L3HD leads to increased fatty acid oxidation and subsequent insulin resistance in the IUGR rat and the L3HD overexpressing transgenic mouse. The identification of a specific mechanism connecting adult disease to an altered intrauterine environment provides insight into the long-term effects of the maternal- fetal milieu. The candidate's long range objectives are to identify and prioritize the molecular mechanisms which are initiated in utero and persist beyond the intrauterine time period, resulting in the altered metabolic state of the adult IUGR individual. The candidate for this Clinical Scientist Development Award is an assistant professor in the Department of Pediatrics at the University of Pittsburgh who maintains clinical and teaching responsibilities. He enjoys a supportive scientific environment as a member of the National Neonatal Developmental and Molecular Biology Group and the Magee-Womens Research Institute whose interest in glucose metabolism and perinatal research respectively converge with his own interests in mitochondrial metabolism. The candidate's commitment towards a research career is demonstrated by his previous participation in the Pediatric Scientist training Program, and his current support through an NICHD supported CHRC award. The CIDA award provides the candidate the time to expand his molecular skills by training him to develop and study transgenic models on both a molecular and physiological level. The career development goals and environment devised by the sponsoring institution have been structured to ensure success in transitioning into an independent investigator.

K08HD001225

1999-01-01

2004-06-30