Currently, around 8% of infants in western countries are born growth-restricted (Mamelle et al., 2006). Epidemiologic studies identified these children as a risk cohort with an increased incidence and prevalence of diseases like arterial hypertension, adiposity and the metabolic syndrome (Varvarigou, 2010). In addition, significant neurodevelopmental disabilities in spatial orientation, executive functioning, inflexibility-creativity, language, short-term memory and school performance have been reported (Leitner et al., 2005; Geva et al., 2006). IUGR children also seem to be at higher risk to develop anxiety disorders (Berle et al., 2006).
Given the importance of early human development on the predisposition for disease in later life, various experimental models have been developed in order to elucidate the mechanistic connection between IUGR and later morbidity (also called “fetal programming”). The rat models of low protein (LP) nutrition (Plank et al., 2006; Nüsken et al., 2011) as well as the bilateral ligation (LIG) of the uterine arteries and veins (Nüsken et al., 2008 and 2011) have been most widely used since they represent the two most common causes for IUGR in humans, which are malnutrition and placental insufficiency (Baschat et al., 2004). Although both models induce a similar IUGR-phenotype, they reflect two pathophysiologically clearly different situations (malnutrition throughout pregnancy vs. operation-related stress and low utero-placental blood flow during terminal pregnancy). In many human studies, a concise pathophysiological classification of IUGR patients is not possible due to the retrospective character of the studies. A differential analysis of IUGR-related disorders by comparison of well-defined experimental IUGR models is therefore a helpful approach to elucidate mechanisms of perinatal programming and to develop therapeutic approaches.
Our aim is to elucidate mechanisms of perinatal programming by different types of intrauterine deficiencies and to develop therapeutic approaches. We put emphasis on a longitudinal design as we believe that programming of disease is a multifactorial process which is relevant in all developmental steps from intrauterine life until at least puberty. Since we come from a clinical background, we have special interest in pursuing perspectives in translational medicine.
- Impact of different causes of intrauterine growth restriction in the rat on early organ development (kidney, brain, heart, vasculature)
- Impact of different causes of intrauterine growth restriction in the rat on long-term organ dysfunction [renal function, endothelial function, neurocognitive outcome (DFG NU 137/3-1)]
- The placenta as a key modulator of perinatal programming - analysis of placental alterations in experimental IUGR models and their implications for fetal programming
- Effect of time limited, post-weaning dietary interventions in the prevention of an adverse long-term outcome (early “re-programming”)
Dr. Kai-Dietrich Nüsken, leader
Dr. Eva Nüsken
Dr. Felix Lechner
Nüsken E, Herrmann Y, Wohlfarth M, Goecke T, Appel S, Schneider H, Dötsch J, Nüsken KD. Leptin regulation in primary human trophoblasts depends on oxygen availability. (In revision)
Nüsken KD, Schneider H, Plank C, Trollmann R, Nüsken E, Rascher W, Dötsch J. Fetal programming of gene expression in growth-restricted rats depends on the cause of low birth weight. Endocrinology. 2011
Plank C, Nüsken KD, Menendez-Castro C, Hartner A, Ostreicher I, Amann K, Baumann P, Peters H, Rascher W, Dötsch J. Intrauterine growth restriction following ligation of the uterine arteries leads to more severe glomerulosclerosis after mesangioproliferative glomerulonephritis in the offspring. Am J Nephrol. 2010
Mühle A, Mühle C, Amann K, Dötsch J, Nüsken KD, Boltze J, Schneider H. No juvenile arterial hypertension in sheep multiples despite reduced nephron numbers. Pediatr Nephrol. 2010
Nüsken KD, Dötsch J, Rauh M, Rascher W, Schneider H. Uteroplacental insufficiency after bilateral uterine artery ligation in the rat: impact on postnatal glucose and lipid metabolism and evidence for metabolic programming of the offspring by sham operation. Endocrinology. 2008
Nüsken KD, Warnecke C, Hilgers KF, Schneider H. Intrauterine growth after uterine artery ligation in rats: dependence on the fetal position in the uterine horn and need for prenatal marking of the animals. J Hypertens. 2007