Development of a novel treatment for hyperbilirubinemia-induced kernicterus

开发治疗高胆红素血症引起的核黄疸的新疗法

基本信息

批准号：
9926721
负责人：
DARIA MOCHLY-ROSEN
金额：
$ 32.94万
依托单位：
STANFORD UNIVERSITY
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926721
关键词：
Address Adult Affect African American Age Aldehydes Animal Model Antioxidants Asians Auditory Basic Science Bilirubin Binding Sites Brain Injuries Cells Cessation of life Clinical Clinical Trials Complex Crystallization Crystallography Cultured Cells Developed Countries Developing Countries Development Drug Screening Enzymes Erythrocytes Family Genes Genetic Diseases Glucosephosphate Dehydrogenase Glucosephosphate Dehydrogenase Deficiency Glutathione Goals Gunn Rats Hemolysis High Prevalence Hospitals Human Hyperbilirubinemia Icterus Impairment In Vitro Incidence Infant Kernicterus Knock-in Letters Measures Modeling Molecular Molecular Chaperones Morbidity - disease rate Motor Mutation Myocardial Infarction NADP Neonatal Nervous System Trauma Neurologic Deficit Neuronal Injury Neurons Neurosciences Neurosciences Research Newborn Infant Parkinson Disease Pathologic Pharmaceutical Chemistry Pharmaceutical Preparations Phototherapy Point Mutation Population Positioning Attribute Predisposition Production Radiodermatitis Rattus Registries Research Risk Rodent Model Roentgen Rays Severities Societies Structural defect Structure Structure-Activity Relationship Testing Time Toxic effect Transgenic Mice Whole Blood Exchange Transfusion aldehyde dehydrogenases clinical care cytotoxicity disability drug development drug discovery epidemiology study experience human disease human model in vivo mortality motor disorder mouse model mutant neurotoxicity novel novel strategies novel therapeutics prevent protein structure public health relevance screening skills small molecule small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic disorder in humans, with more than 160 point mutations in this gene, and over 400 million people affected. Although most research relates to G6PD deficiency and increased hemolysis (breakdown of red blood cells) and accumulation of bilirubin in adults, epidemiological studies indicate that G6PD deficiency is also a major cause of pathologic neonatal bilirubin accumulation (jaundice) and a contributor to morbidity, including neurological injury (kernicterus). The hypothesis to be tested here is that correcting the activity and stability of G6PD mutants as well as increasing the activity of the wild-type enzyme will decrease bilirubin-induced neurotoxicity in infants. In this proposal, the plan to begin developing a treatment for kernicterus using a totally novel approach, by developing activators of wild-type (Wt) and mutant G6PDs is described. The project includes four aims: AIM 1: Identify small molecule chaperones that increase the catalytic activity of Wt and common G6PD mutants using an in vitro screen of a library of small molecules. AIM 2: Determine the X-ray crystal structure of the Wt and mutant G6PD enzymes in complex with the G6PD chaperone(s). Aim 3: Evaluate the ability of the chaperone(s) to protect cultured cells expressing Wt or the mutant G6PDs from bilirubin-induced cytotoxicity and elucidate the molecular basis of their effects. AIM 4: Evaluate the ability of the small molecule chaperone(s) to reduce bilirubin-induced neurotoxicity in rodent models of newborn hyperbilirubinemia, in vivo. Two established rat models of kernicterus (Gunn rats and bilirubin-injected Wt rats) and three new mouse models [transgenic mice, mimicking three common G6PD mutations with kernicterus] will be used. Small molecules, identified in Aim 3 to protect neurons from bilirubin-induced toxicity, will be tested for their ability to prevent or reduce neurological injury (measured as loss of motor and auditory skills) due to hyperbilirubinemia in one or more of these rodent models, in vivo. The experience of Dr. Stevenson (co-PI) in basic research related to hyperbilirubinemia and in clinical care of such newborns, the expertise of Dr. Wakatsuki in crystallography, together with our expertise in drug discovery and development and in neuroscience research, and the expertise of other advisors in drug screening, medicinal chemistry, in gene editing and in assessing auditory and motor dysfunctions, place the team in a unique position to address the above goals.

描述（由适用提供）：6-磷酸葡萄糖脱氢酶（G6PD）缺乏症是人类最常见的遗传疾病，该基因中有超过160点突变，受影响超过4亿人。尽管大多数研究与G6PD缺乏症和溶血增加（红细胞崩溃）和胆红素在成人中的积累，但流行病学研究表明，G6PD缺乏症也是病理新生儿胆红素积累（Jaundice）（Jaundice）（Jaundice）的主要原因（Jaundice）和对疾病的贡献，包括神经系统损伤（包括神经系统损伤）。这里要检验的假设是纠正活动 G6PD突变体的稳定性以及增加野生型酶的活性将降低婴儿胆红素诱导的神经毒性。在此提案中，开始制定的计划描述了使用一种完全新颖的方法对核的处理，通过开发野生型（WT）和突变体G6PD的激活剂。该项目包括四个目的：目标1：识别小分子链酮，使用小分子库的体外筛选来增加WT和常见G6PD突变体的催化活性。目标2：确定与G6PD AIM 3中WT和突变体G6PD酶的X射线晶体结构3：评估链酮保护表达WT的培养细胞或突变G6PD的能力，从而免受胆红素诱导的细胞毒性的能力，并降低其效果的分子基础。 AIM 4：评估小分子伴侣（S）在体内降低胆红素诱导的神经毒性的能力。将使用两种已建立的大鼠模型（Gunn大鼠和胆红素注射的WT大鼠）和三种新的小鼠模型[转基因小鼠，模仿三个常见的G6PD突变，用核心使用]。在AIM 3中鉴定出的小分子以保护神经元免受胆红素诱导的毒性的影响，该测试将因其预防或减少神经系统损伤（以运动和听觉技能的丧失而衡量）的能力，这是由于高胆红素和多个啮齿动物模型中的高胆红素血症。 The experience of Dr. Stevenson (co-PI) in basic research related to hyperbilirubinemia and in clinical care of such newborns, the expertise of Dr. Wakatsuki in crystallography, together with our expertise in drug discovery and development and in neuroscience research, and the expertise of other advisors in drug screening, medical chemistry, in gene editing and in assessment auditory and motor dysfunctions, place the team in a unique position to address the above目标。