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The Role of Lipid Rafts in Billirubin Neurotoxicity

脂筏在胆红素神经毒性中的作用

基本信息

批准号：
9244807
负责人：
CYNTHIA FRANCES BEARER
金额：
$ 19.46万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244807
关键词：
Abnormal coordination Acute Address Affect Affinity Albumins Apoptosis Basal Ganglia Betaine Bilirubin Binding Biochemical Biological Assay Blood - brain barrier anatomy Brain region Caveolins Cell membrane Cerebellar Diseases Cerebellum Cholesterol Choline Chronic Clinical Cytoplasmic Granules DNA Methylation Data Development Dietary Intervention Equilibrium Experimental Models Exposure to Foundations Functional disorder Funding Ganglioside GM1 Gene Expression Glucuronic Acids Gunn Rats Hearing problem Heme High Prevalence Hyperbilirubinemia In Vitro Injection of therapeutic agent Intervention Kernicterus Knowledge Laminin Lead Lecithin MAPK3 gene Measures Mediating Membrane Microdomains Methionine Modeling Motor Movement Movement Disorders Neural Cell Adhesion Molecule L1 Neuraxis Neurites Neurodevelopmental Deficit Neurologic Dysfunctions Neurons Neurotoxins Pathway interactions Phospholipids Phototherapy Plasma Play Pregnancy Premature Infant Proteins RNA methylation Rattus Receptor Signaling Reporter Research Role Rotarod Performance Test Seizures Severities Signal Pathway Signal Transduction Signaling Protein Small Interfering RNA Sphingomyelins Sum Symptoms Syndrome Testing Therapeutic Tubulin United States Weight Work acute symptom behavior test behavioral outcome brain cell cell type choline supplementation comparative effectiveness equilibration disorder high risk histone methylation in vivo knockout animal neurotoxicity novel persistent symptom postnatal preterm newborn prevent protein protein interaction protein transport public health relevance pup ranpirnase receptor total measurement Bilirubin

项目摘要

DESCRIPTION (provided by applicant): Bilirubin, the breakdown product of heme, is a known neurotoxicant. In the United States, hyperbilirubinemia occurs in almost all preterm neonates <35 weeks gestation. In preterm infants, it is unknown at what level bilirubin causes neurodevelopmental harm. Bilirubin rises to a level where the unconjugated free bilirubin (Bf) concentration exceeds the plasma's capacity to bind it. Then, Bf crosses the blood brain barrier and binds to its targets including the phospholipids of neurons. Once Bf crosses the blood brain barrier, the clinical syndrome of bilirubin-induced neurologic dysfunction can occur. Acute symptoms include high pitched cry, seizures, and hypo- or hypertonicity, whereas chronic symptoms include disturbed movement and balance. Despite the high prevalence of hyperbilirubinemia, the mechanisms underlying the effects of Bf on neuronal function are poorly understood. The affinity of Bf with neuronal phospholipids suggests that lipid rafts might be a major target in hyperbilirubinemia. Lipid rafts are specialized dynamic microdomains of the plasma membrane containing cholesterol as well as the phospholipid sphingomyelin. They promote protein-protein interactions and facilitate signaling and protein trafficking. For example, lipid rafts play a major role on L1 cell adhesion molecule (L1) mediated neurite outgrowth, a crucial step in cerebellar development that depends on both signal transduction and protein trafficking. Our preliminary results show that bilirubin inhibits lipid raft function using L1 as a reporter. In addition, our prior work shows that lipid raft dysfunction can be reduced with supplementation of choline, a precursor of phosphatidylcholine and sphingomyelin. Our novel hypotheses are that 1) free unconjugated bilirubin binds to and causes lipid raft dysfunction, resulting in cerebellar dysfunction; and 2) supplementation with choline will reduce these effects. We will address these hypotheses using both the well established model of cultured cerebellar granule neurons from postnatal day 6 heterozygous Gunn rat pups and the sulfadimethoxine treated homozygous Gunn rat as an in vivo rat pup model. We will use L1, the GABAA receptor, β III tubulin, flotilin and caveolin as reporter proteins to test lipid raft functon in cerebellar granule neurons (CGN) in vitro and in Gunn rat pups in vivo, determine cerebellar weight and test behavioral outcomes: both the constant and accelerating rotarod test. We will test our hypotheses using two specific aims: The first aim will determine if bilirubin accumulates within lipid rafts and its effects on functions of lipid rafts and apoptosis. The effect of choline supplementation on these effects of bilirubin will be determined. In the second aim, the effect of bilirubin on cerebellar weight and cerebellar function will be measured, and the effect of pretreatment with choline determined.