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The genetic response to neurotoxic bilirubin in jaundiced rats before and after administration of bilirubin-displacing drugs
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abstract
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Some form of visible jaundice occurs in 60–80% of all newborns and is the result of elevated bilirubin levels in blood (hyperbilirubinemia). A small portion of these infants develop severe jaundice and are at risk to develop brain damage due to bilirubin neurotoxicity, known as kernicterus. Bilirubin is normally safely bound to albumin in the blood but during times of severe jaundice, the toxic form of unbound, “free” bilirubin (Bf) increases, exceed the binding capacity of blood albumin and other proteins, and deposits into tissues including the brain. While there are genetic mutations linked to a state of hyperbilirubinemia, little is known about how bilirubin damages brain and what the genetic response is to this toxicity at the cellular level. The goal of this project is to define the genetic response to bilirubin neurotoxicity in vivo with the long-term objective of discovering actionable genetic targets that could augment current methods to improve treatment of severe jaundice and prevent kernicterus. Specific Aim 1, will determine the relationship between blood Bf, bilirubin deposition and damage to the brain using the Gunn rat model. The Gunn rat is a classic model for studying hyperbilirubinemia and kernicterus, but due to challenges in measuring Bf in rodent blood, the relationship between total bilirubin measurements in the blood and Bf deposition in the brain have never been thoroughly described. These data will not only assist in describing the mechanism of neurotoxicity in the Gunn rat, but they could also help predict when and how much damage is occurring in a similar clinical scenario. Specific Aim 2, will identify the patterns of expression that differ in protected vs. susceptible regions of the brain before and after bilirubin exposure in the Gunn rat model using next-generation RNA sequencing (RNA Seq). This hypothesis-generating screen will identify those genes with significant differences in gene expression between protected and sensitive regions of the Gunn rat brain. These data will not only shed light on the mechanism(s) of bilirubin neurotoxicity but it will also provide a list of targets for manipulation to improve the outcomes of newborns experiencing severe jaundice
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