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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（由申请人提供）：葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏症是人类最常见的遗传性疾病，该基因有160多个点突变，超过4亿人受到影响。虽然大多数研究涉及G6 PD缺乏症和增加溶血（红细胞的分解）和胆红素在成人中的积累，流行病学研究表明，G6 PD缺乏症也是病理性新生儿胆红素积累（黄疸）的主要原因，并导致发病，包括神经损伤（核黄疸）。这里要检验的假设是， G6 PD突变体的稳定性以及野生型酶活性的增加将降低婴儿中胆红素诱导的神经毒性。在这份提案中，计划开始发展描述了一种通过开发野生型（Wt）和突变型G6 PD的激活剂，使用全新方法治疗核黄疸的方法。该项目包括四个目标：目的1：使用小分子文库的体外筛选来鉴定增加Wt和常见G6 PD突变体的催化活性的小分子伴侣。目的2：确定Wt和突变型G6 PD酶与G6 PD分子伴侣复合物的X-射线晶体结构。目标3：评价分子伴侣保护表达Wt或突变型G6 PD的培养细胞免受胆红素诱导的细胞毒性的能力，并阐明其作用的分子基础。目标4：在体内新生儿高胆红素血症啮齿动物模型中评估小分子伴侣降低胆红素诱导的神经毒性的能力。将使用两种已建立的核黄疸大鼠模型（古恩大鼠和注射胆红素的Wt大鼠）和三种新的小鼠模型[转基因小鼠，模拟核黄疸的三种常见G6 PD突变]。将在一种或多种这些啮齿动物模型中体内检测目标3中确定的保护神经元免受胆红素诱导毒性的小分子预防或减少高胆红素血症所致神经损伤（测量为运动和听觉技能丧失）的能力。史蒂文森博士（共同主要研究者）在高胆红素血症相关基础研究和此类新生儿临床护理方面的经验，Wakatsuki博士在晶体学方面的专业知识，以及我们在药物发现和开发以及神经科学研究方面的专业知识，以及其他顾问在药物筛选、药物化学、基因编辑以及评估听觉和运动功能障碍方面的专业知识，使团队处于独特的位置，以实现上述目标。