2007-2008 Recipients

Regulation of E2F1-Induced Apoptosis by the PI3K pathway in Retinoblastoma

Retinoblastoma is a malignancy of the retina that most often occurs in younger children under the age of five years and is the third most common malignancy in infants under one year of age after neuroblastoma and leukemia.  This disease is caused by the inactivation of the Retinoblastoma (Rb) tumor suppressor gene which is functionally disrupted in most, if not all, tumors.  Rb regulation of cell cycle progression and tumorigenesis is dependent on its control of E2F transcription factor function, a family of proteins that control expression of genes required for proliferation.  Further work has highlighted the role of E2F proteins, particularly E2F1, in forming the link between the deregulation of Rb pathway activity and induction of p53-dependent apoptosis to suppress tumorigenesis.  An important, unanswered question is how E2F1 induced apoptosis seen in the context of Rb pathway mutation is suppressed during normal growth stimulation and tumorigenesis.  We have shown that E2F1 induced apoptosis is blocked by PI3K and Akt survival signaling induced following normal cell growth.  This research project will determine which PI3K regulated pathway components inhibit E2F1 apoptosis induction, test the extent to which the PI3K pathway controls retinoblastoma formation in vivo, and develop strategies to restore E2F1 apoptosis induction in retinoblastoma.

Novel Methods of Quantifying Endothelial Activation in Children

The process of atherosclerotic cardiovascular disease begins in childhood.  Identifying high-risk children is challenging since risk factor burden varies and current non-invasive methods used to quantify vascular health demonstrate high measurement variability and poor clinical feasibility.  In adults, circulating endothelial cells and endothelial microparticles have emerged as potentially useful measures of endothelial activation.  The value of measuring these cells for risk stratification in potentially high-risk children is unknown.  The purpose of the proposed project is to evaluate the utility of circulating endothelial cells and endothelial microparticles as non-invasive markers of endothelial activation in overweight children with cardiometabolic risk factors.  Forty-eight children and adolescents will be recruited from an ongoing study at the University of Minnesota assessing the role of body fatness and insulin resistance as mediators of cardiometabolic risk.  Circulating endothelial cells and endothelial microparticles will be measured via flow cytometry at the University of Minnesota Vascular Biology Center.  We hypothesize that the number of endothelial cells will be correlated with the magnitude of obesity and insulin resistance and that cell number will be significantly associated with cardiometabolic risk factors.

Neuroprotective Role of B-Hydroxybutyrate During Hypoglycemia in Developing Rats

Hypoglycemia (low glucose concentrations in the blood) is a complication of intensive insulin therapy in children with type 1 diabetes. Since the brain depends on glucose for its energy needs, there are concerns that severe and recurrent hypoglycemia may have an adverse impact on neurodevelopment. Unfortunately, neither the mechanisms of hypoglycemic brain injury, nor whether non-glucose substrates, such as beta-hydroxybutyrate, provide better neuroprotection than the conventionally used glucose during hypoglycemia have not been well studied. The proposed preclinical research will comprehensively establish the mechanisms of recurrent hypoglycemia-induced regional brain injury using 1H NMR spectroscopy and histochemical methods, and demonstrate the neuroprotective role of beta-hydroxybutyrate. The rationale for this research is that establishing the neuroprotective role of beta-hydroxybutyrate would lessen the concerns for hypoglycemia-induced brain injury and permit intensive insulin therapy in children with type 1 diabetes. Thus, the results of the study will have a positive impact on the management of these children. Moreover, the research findings will advance the field of neuroprotection in other populations at risk for hypoglycemia, such as newborn infants, and adolescents and adults with type 1 or 2 diabetes.

Molecular Testing for Congenital CMV Infection in Newborn Blood Spots of Infants who Died of SIDS

Sudden infant death syndrome (SIDS) is the leading cause of death in the first year of life. Little is known regarding the pathogenesis and etiology of this significant cause of infant mortality. Infection with cytomegalovirus (CMV), which is the most common congenital viral infection, is known to cause a wide spectrum of diseases, most commonly sensorineural hearing loss (SNHL). Recent evidence that suggests abnormal newborn hearing screen (NBHS) as a risk factor for SIDS may provides a potential clue regarding possible association between congenital CMV and infant mortality. By testing their newborn blood spots (NBS) for CMV DNA, Dr Sharon will test the hypothesis that infants who died of SIDS were more likely to be born with CMV infection as compared to a control cohort. This unique collaboration between academic and state health department partners will increase knowledge about the potential impact of CMV infection on unexplained infant death.

Ashajyothi M Siddappa, M.D.
Department of Pediatrics

Effect of Prenatal Choline Supplementation in Perinatal Iron Deficiency on Hippocampal Dendritic Morphology and Gene Expression

Iron deficiency is a common nutrient deficiency affecting two billion people in the world. Iron is vital for early brain development and function. Iron forms an important part of enzyme systems involved in energy metabolism, myelination, and neurotransmitter synthesis. Animal studies have shown impaired energy metabolism, neurochemical profile, dendritic morphology, gene expression and behavior in perinatal iron deficiency, which persist into adulthood in spite of iron treatment. Choline is a nutrient that is abundant in common diets (e.g. eggs), is easily supplemented during pregnancy and is crucial for early brain development. Choline is a precursor of phospholipids, which forms an important component of neuronal cell membrane, is needed for axonal formation and for establishment of cell-to-cell interaction during critical period of development. Choline enhances working memory, hippocampal long-term potentiation, structure and function of hippocampal pyramidal neurons. Studies have shown long lasting positive effects of prenatal choline supplementation (beyond sufficiency) on cognitive function mediated by the hippocampus. The aim of our study is to examine whether prenatal supplementation of choline in addition to iron can decrease or mitigate the effects of iron deficiency on dendritic morphology and gene expression in developing rat brain.

Sing Sing Way, M.D., Ph.D.
Division of Pediatric Infectious Disease

Control of CD4 T cell differentiation and lineage stability by T cell receptor-peptide affinity

On a global scale, infectious diseases as a group remain the leading cause of mortality for infants, children, and adults despite the widespread implementation of many highly effective vaccines. A primary limitation in our current armament of vaccines is that they confer primarily through the production of protective antibody, however antibody cannot enter the intracellular compartment of infected cells. Accordingly, many important infections for which no effective vaccine exists reside primarily in the intracellular compartment of infected cells. Protection from intracellular pathogens requires vaccines that prime and activate T cells in an antigen specific manner. Activation and differentiation of CD4 T cells requires at least three inter-related signals. Stimulation by peptide + MHC through the TCR provides signal 1, by costimulatory molecules signal 2, and various inflammatory cytokines signal 3. Although each of these signals can play important roles in T cell differentiation, their relative importance especially during the context of in vivo infection is unknown. Moreover, while peptide TCR affinity can impact the Th1 versus Th2 differentiation pattern of naive T cells, the role of peptide TCR affinity to Th17 differentiation is unclear. Therefore, for this project funded by the Viking's Children's Fund, we will examine the role of peptide TCR affinity on CD4 T cell differentiation and lineage commitment stability after T cell activation during experimental in vivo infection.