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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.

先天性高胰岛素血症（HI）是婴儿持续性低血糖的最常见原因，孩子患有HI的儿童有癫痫发作和永久性脑损伤的高风险，低血糖是非常困难的。最近的研究表明，HI与遗传缺陷有关，调节β细胞胰岛素分泌的途径。虽然已经发现了9个这样的位点，但许多HI儿童这些基因没有可识别的突变。这包括三分之一的弥漫性HI病例，胰腺切除术和一半的病例对二氮嗪的药物治疗有反应。我们的假设是这些儿童的高胰岛素血症既涉及已知基因座的新分子缺陷，以前未被发现的新基因位点。这项研究的长期目标是确定基因型- 这些疾病的表型相关性，以指导诊断和治疗，并发现新的形式，先天性高胰岛素血症我将扩展和扩大新的遗传位点的研究， McQuarrie在1954年报道的具有重要历史意义的显性HI家族中的高胰岛素血症。临床表型分析、连锁分析和下一代测序方法已经将HK 1确定为可能的候选者基因这将通过招募额外的谱系和功能测定来证实。目标2将在我们大量的二氮嗪患儿中，没有可识别的突变的反应性高胰岛素血症。我们将试图找出后合子已知基因座或新的额外基因座的突变，使用靶向下一代测序方法。目标3将继续我们的努力，以确定机制的分子缺陷的儿童谁没有反应，二氮嗪并需要胰腺切除术。我们将寻找这两个基因的新的隐蔽或嵌合突变， Llp上的相邻基因负责大多数这种形式的HI病例：ABCC 8/SUR 1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中识别合子后嵌合突变;非编码突变区域和microRNA位点;或表观遗传甲基化缺陷。相关性（参见说明）：这个转化研究项目旨在确定先天性高胰岛素血症的分子原因低血糖（HI）。新的候选基因将使用下一代DNA测序和先进的研究需要胰腺切除术的儿童胰岛的显微方法。结果将改善治疗儿童HI，并提供新的见解，调节正常人的胰岛素分泌。