Date of Award

January 2013

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joseph Madri

Subject Area(s)

Medicine

Abstract

The need to accurately predict the ability of a prematurely born infant to recover from hypoxia induced damage associated with prematurity is rooted in our need to develop better interventions, with fewer side-effects, with which to treat these complicated patients. Previous work done in murine models mimicking hypoxia induced damage and its neurological sequelae have suggested hypoxia induced factor-1alpha; (HIF-1alpha), and its downstream effector molecules, brain derived neurotrophic factor (BDNF) and stromal derived factor-1 (SDF-1), may play an integral role in protecting the developing brain from the deleterious effects of low O2. Moreover, a number of single nucleotide polymorphisms (SNPs) have been identified, which affect the expression of these proteins on an individual basis. To that end, we hypothesized that BDNF expression levels gathered from venous cord blood, and genetic analysis for the presence of the rs6265 and rs1801157 SNPs in the BDNF and SDF-1 genes could be used as biochemical and genetic biomarkers to predict short term neonatal outcomes in premature infants born at Yale New Haven Hospital.

BDNF levels, determined by quantitative ELISA in 23 patients, and the presence of SNPs, determined in duplicate by restriction fragment length polymorphism assay and Sanger sequencing in 53 patients, were correlated with the development of a variety of neonatal outcomes. Our results indicated that although not statistically significant, the development of bronchopulmonary dysplasia, necrtotizing enterocolitis, and early onset neonatal sepsis (EONS) trended towards an association with lower cord blood BDNF levels (p-values <0.10). Likewise, the presence of the rs6265 SNP appeared to be protective against the development of culture positive EONS (p < 0.08), while the presence of rs1801157 SNP appeared to be protective against the development of clinical EONS. Taken together, these data suggest that while cord blood BDNF levels and the presence of the rs6265 and rs1801157 SNPs show potential as useful molecular and genetic biomarkers for predicting outcomes of premature infants, the association between these factors and neonatal outcomes is not strong enough for the number of patients examined in this study to provide conclusive results of the utility of these biomarkers in guiding clinical decision making. Consequently, further research of these, and other, biomarkers is necessary to better elucidate their usefulness.

Comments

This is an Open Access Thesis.

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