Epigenetic Control of Human Beta Cell Proliferation

人类β细胞增殖的表观遗传控制

基本信息

批准号：
9883790
负责人：
Carmen Argmann
金额：
$ 63.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883790
关键词：
3-Dimensional Address Adult Alleles Architecture B-Lymphocytes Beckwith-Wiedemann Syndrome Benign Beta Cell Bioinformatics Biology Blood Vessels Categories Cell Proliferation Cell physiology Cells Chromatin Chromosome 11 Chromosomes, Human, 13-15 Collection Complex Copy Number Polymorphism DNA DNA Methylation DNA Sequence Alteration Diabetes Mellitus Disease Drug Targeting EZH2 gene Enzymes Epigenetic Process Event Excision Experimental Models Fibroblasts Functional disorder Gene Expression Genes Genomics Goals Harmine Histology Human Hyperinsulinism Insulin Insulin deficiency Insulin-Dependent Diabetes Mellitus Knowledge Lead Loss of Heterozygosity Methods Methylation Modeling Mutation Nature Non-Insulin-Dependent Diabetes Mellitus Pancreas Pancreatic Adenoma Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Polycomb RNA Recipe Reproducibility Resistance Retrieval Rodent Series Structural defect Structure Surface Therapeutic Time Variant X-Ray Computed Tomography analog biobank cell regeneration drug discovery imprint insulinoma kinase inhibitor member methylome news novel regenerative small molecule three dimensional structure transcriptome transcriptome sequencing transcriptomics

项目摘要

All forms of diabetes are due to a relative deficit of functional beta cells, yet adult human beta cells are resistant to attempts at replication, and serve as a poor experimental model for replicating human beta cells. Because of this paucity of models for adult human beta cell replication, we have developed a large Biorepository of rare human insulinomas, benign pancreatic adenomas that grow and over-secrete insulin, believing that they may provide information that will inform attempts at clues and drug targets and pathways for therapeutic human beta cell regeneration. Recently, we have provided the results of intensive genomic, transcriptomic and bioinformatic analysis of human insulinomas, comparing them to FACS-sorted pure human beta cells. Remarkably, we find that insulinomas display three cardinal features: 1) they almost universally contain recurring mutations, copy number alterations and gene expression abnormalities in members of the Trithorax Group of chromatin modifying enzymes, notably including KDM6A, MLL3 and/or MEN1; 2) they also almost universally display alterations in the Polycomb Repressive Complex of chromatin modifying enzymes and their targets, particularly YY1, EZH2 and H3F3A; 3) they almost universally display abnormalities in the chromosome 11, such as allelic loss of all or part of chromosome 11, and/or allele-specific expression and/or DNA methylation/imprinting abnormalities of the imprinted 11p15 region of chromosome 11, reminiscent of the other beta cell proliferative disorders, such as the Focal Variant of Hyperinsulinism and Beckwith-Wiedemann Syndrome. On the other hand, the mechanisms through with these events lead to beta cell proliferation and while maintaining the beta cell phenotype are unknown. More specifically, exactly how MEN1, KDM6A, MLL3, YY1, EZH2 and H3F3A modulate beta cell function and proliferation are largely unknown. The three Specific Aims of this application address this important knowledge gap. Aim 1. To Elucidate the Abnormal Pathobiology of Three Key Trithorax Members In Insulinoma vs. Beta Cells. Aim 2. To Define Abnormal Biology of Three Key Polycomb Repressive Complex Members in Insulinomas vs. Beta Cells. Aim 3. To Define 3-D Chromosome 11p15 Architecture in Insulinomas and Beta Cells.

所有形式的糖尿病都是由于功能性β细胞的相对缺陷，但是成年人类β细胞对尝试复制的尝试具有抵抗力，并且是复制人β细胞的差实验模型。由于对于成年人β细胞复制的模型很少，我们开发了大型的生物疗法，这些生物疗法是罕见的人类胰岛素，良性胰腺腺瘤，这些胰岛胰岛素生长和过度分泌胰岛素，他们认为它们可能会提供有关治疗性人类beta beta Cell Cell Renteration的线索和药物目标和药物目标尝试的信息。最近，我们提供了对人胰岛素瘤的密集基因组，转录组和生物信息学分析的结果，将其与FACS分类的纯人β细胞进行了比较。值得注意的是，我们发现胰岛素瘤显示三个基本特征：1）它们几乎普遍包含重复出现的突变，拷贝数改变和基因表达异常，染色质修饰酶的成员，特别是包括KDM6A，MLL3和/或MEN1； 2）它们还几乎普遍显示在染色质修饰酶及其靶标的Polycomb抑制作用中，尤其是YY1，EZH2和H3F3A； 3）它们在11号染色体中几乎普遍显示异常，例如染色体11的全部或一部分的等位基因损失，以及/或等位基因特异性表达和/或DNA甲基化/DNA甲基化/烙印的异常，11P15染色体11P15染色体区域，让人联想到其他Beta细胞增殖症和诸如其他偶然的变体，例如贝克维斯·威德曼综合症。另一方面，这些事件通过这些事件的机制导致β细胞增殖，同时保持β细胞表型是未知的。更具体地说，确切地说，MEN1，KDM6A，MLL3，YY1，EZH2和H3F3A如何调节β细胞功能和增殖在很大程度上未知。本申请的三个特定目的解决了这一重要知识差距。目的1。阐明胰岛素瘤与β细胞中三个关键三曲霉成员的病理生物学异常。目的2。定义胰岛细胞与β细胞中三个关键多型抑制复合成员的异常生物学。目的3。定义胰岛素和β细胞中的3-D染色体11P15结构。