Islet Dysregulation in Infants with Congenital Hyperinsulinism

先天性高胰岛素血症婴儿的胰岛失调

基本信息

批准号：
8764054
负责人：
CHARLES ALFRED STANLEY
金额：
$ 71.79万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764054
关键词：
10q21 11p 11q 8 year old AKT2 gene Accounting Acyl CoA Dehydrogenases Address Adult Adverse effects Affect Affinity Africa South of the Sahara African American Age Alleles Alpha Cell American Amino Acids Aneuploidy Appearance Area Asia Attention Australia Award Bar Codes Beckwith-Wiedemann Syndrome Beta Cell Binding Binding Sites Biological Assay Books Brain Injuries Brothers CDKN1C gene Calcium Calcium Signaling Candidate Disease Gene Cataloging Catalogs Cell membrane Cell physiology Child Childhood Chromosomes, Human, Pair 11 Clinical Clinical Research Code Collaborations Complementary DNA Computer Simulation Congenital Abnormality Congestive DNA DNA Sequence DNA replicase Data Data Analyses Defect Development Diabetes Mellitus Diagnosis Diazoxide Dideoxy Chain Termination DNA Sequencing Diffuse Disease Distal Dominant Genes Dominant-Negative Mutation Duct (organ) structure Dumping Syndrome Electrophoretic Mobility Shift Assay Endocrine Endocrinology England Epigallocatechin Gallate Epigenetic Process Etiology Europe European Excision Exercise Failure Family Family history of Family member Fanconi Syndrome Fasting Fathers Fibroblasts Freezing Frequencies Fructokinases Functional RNA Future GLUT2 gene Gene Mutation Generations Genes Genetic Genome Genomic DNA Genotype Glucagon Glucokinase Glucose Glucose Plasma Concentration Glycogen Glycolysis Goals Grant Guidelines Haplotypes Head of pancreas Histologic Histology Hormones Human Hyperammonemia Hyperinsulinism Hypertrophic Cardiomyopathy Hypertrophy Hypoglycemia IRS1 gene In Vitro Incidence Individual Infant Inherited Instruction Insulin International Intestines Intussusception Investigation Ions Islet Cell Islets of Langerhans Italy Joints Journals Kidney Label Lesion Life Link Literature Lithium Chloride Liver Liver Dysfunction Longitudinal Studies Loss of Heterozygosity Lymphocyte Manuscripts Measures Mediator of activation protein Medical Medicine Methods Methylation MicroRNAs Microarray Analysis Missense Mutation Mitochondrial DNA Modeling Molecular Molecular Analysis Molecular Genetics Mono-S Monograph Morbidity - disease rate Mosaicism Mutation Mutation Analysis Mutation Detection Nature Necrotizing Enterocolitis Negative Staining Neurologic New England Newborn Infant Normal tissue morphology North America Nuclear Octreotide Oncogenes Operative Surgical Procedures Oral Organ Other Genetics PIK3CA gene Pancreas Pancreatectomy Paper Paris, France Pathogenesis Pathology Pathway interactions Patients Pattern Pediatric Hospitals Pediatrics Peripheral Blood Mononuclear Cell Persistent Hyperinsulinemia Hypoglycemia of Infancy Pharmaceutical Preparations Pharmacotherapy Phenotype Philadelphia Phosphoglucomutase Physiological Play Positron-Emission Tomography Preparation Principal Investigator Procedures Progress Reports Promoter Regions Protein Binding Proteins Publications Publishing Reaction Recruitment Activity Regulation Reporting Research Research Personnel Research Project Grants Resectable Resected Resistance Resolution Rett Syndrome Risk Role Route Roux-en-Y Anastomosis Sampling Scanning Seizures Series Sister Site Societies South America Specificity Staining method Stains Subgroup Syndrome Tail Techniques Testing Time TimeLine Tissues Trans-Activators Transcriptional Regulation Translational Research Travel Tumor Suppressor Proteins Turner&apos s Syndrome UCP2 protein Validation Variant Work Writing X Chromosome Zinc abstracting acyl-CoA dehydrogenase base cleft lip and palate clinical phenotype design disease-causing mutation editorial epigenetic marker exome exome sequencing experience gain of function mutation gamma hydroxybutyrate gamma-Aminobutyric Acid genetic association genetic linkage analysis genetic pedigree genome sequencing glucagon-like peptide 1 glucose metabolism glycosylation hexokinase high risk imprint improved induced pluripotent stem cell infancy infant of diabetic mother inhibitor/antagonist insertion/deletion mutation insight insulin secretion insulin signaling insulinoma interest islet lectures meetings mortality mouse model mutant neonate new technology next generation sequencing novel offspring paracrine partial response peripheral blood preclinical study prevent programs promoter receptor research study response screening shunt pathway standard of care success symposium trafficking transcription factor transcription factor CP2 transcriptome sequencing transmission process tumor tumor growth

项目摘要

Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Children with HI are at high risk of seizures and permanent brain damage and treatment of their hypoglycemia is extremely difficult. Recent work has shown that HI is associated with genetic defects in the pathways regulating beta-cell insulin secretion. Although 9 such loci have been found, many children with HI have no identifiable mutation of these genes. This includes one-third of diffuse HI cases that require pancreatectomy and half of cases that are responsive to medical treatment with diazoxide. Our hypothesis is that hyperinsulinism in these groups of children involves both novel molecular defects of known loci, as well as, previously unrecognized new genetic loci. The long-term goals of the research are to identify genotype- phenotype correlations in these disorders to guide diagnosis and treatment and to uncover new forms of congenital hyperinsulinism. A i m i will extend and expand studies of the novel genetic locus for hyperinsulinism in the historically-important dominant HI family reported by McQuarrie in 1954. Clinical phenotyping, linkage analysis, and next-gen sequencing methods have identified HK1 as a likely candidate gene. This will be confirmed by recruitment of additional pedigrees and by functional assays. Aim 2 will extend the search for defects in novel candidate genes in our large series of children with diazoxide responsive hyperinsulinism that have no identifiable mutation. We will seek to identify either post-zygotic mutations of known loci or novel additional loci using targeted next-gen sequencing methods. Aim 3 will continue our efforts to define the mechanisms of molecular defects in children who fail to respond to diazoxide and require pancreatectomy. We will search for novel cryptic or mosaic mutations of the two adjacent genes on l i p that are responsible for most cases of this form of HI: ABCC8/SUR1 and KCNJ11/Kir6.2. This will include functional testing of insulin release and molecular analysis of cultured islets from patients undergoing surgery to identify post-zygotic, mosaic mutations; mutations in non-coding regions, and microRNA sites; or epigenetic methylation defects. RELEVANCE (See instructions): This translational research project seeks to define the molecular causes of congenital hyperinsulinemic hypoglycemia (HI). Novel candidate genes will be sought using next-gen DNA sequencing and advanced micro-methods to study pancreatic islets from children requiring pancreatectomy. The results will improve the treatment of children with HI and provide new insight into regulation of insulin secretion in normal humans.

先天性高胰岛素（HI）是婴儿持续性低血糖症的最常见原因孩子们。 HI的儿童有癫痫发作的高风险和永久性的脑损伤和治疗低血糖极为困难。最近的工作表明，HI与遗传缺陷有关调节β细胞胰岛素分泌的途径。尽管发现了9个基因座，但许多患有HI的孩子这些基因没有可识别的突变。这包括需要的三分之一需要胰腺切除术和一半对用二氮杂治疗的病例。我们的假设是这些儿童组中的超胰岛素主义既涉及已知基因座的新分子缺陷，也涉及 AS，以前未被认可的新遗传基因座。该研究的长期目标是确定基因型 - 这些疾病中的表型相关性，以指导诊断和治疗，并发现新形式先天性高胰岛素主义。我将扩展并扩展对新型遗传基因座的研究麦卡里（McQuarrie）在1954年报道的历史上重要的主要hi家族中的超胰岛素主义。临床表型，链接分析和下一代测序方法已将HK1识别为可能的候选者基因。这将通过募集其他血统和功能分析来确认这一点。 AIM 2意志在我们的大型二氮氧化物儿童中，扩展在新型候选基因中寻找缺陷的搜索反应迅速的超胰岛素主义，没有可识别的突变。我们将寻求确定两种后结肠使用靶向下一代测序方法的已知基因座或新型基因座的突变。目标3意志继续我们的努力来定义未能反应的儿童分子缺陷的机制二氮氧化物，需要胰腺切除术。我们将搜索两者的新颖隐秘或镶嵌突变 L i p上的相邻基因负责这种形式的HI：ABCC8/SUR1和 KCNJ11/KIR6.2。这将包括胰岛素释放的功能测试和培养胰岛的分子分析从接受手术的患者来鉴定骨气后的镶嵌突变；非编码中的突变区域和microRNA站点；或表观遗传甲基化缺陷。相关性（请参阅说明）：这个翻译研究项目旨在定义先天性高胰岛素的分子原因低血糖（HI）。新的候选基因将使用下一代DNA测序和先进从需要胰腺切除术的儿童研究胰岛的微方法。结果将改善治疗HI的儿童，并为正常人的胰岛素分泌调节提供了新的见解。