DREAM Complex Maintenance of Human Beta Cell Quiescence

DREAM 复合物维持人类 β 细胞静止

基本信息

批准号：
10267388
负责人：
ANDREW F. STEWART
金额：
$ 61.53万
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：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267388
关键词：
Adult Affect Agonist American Beta Cell CCNE1 gene CDC2 gene CDKN1A gene CDKN1C gene CREBBP gene Calcium Calcium Channel Cell Count Cell Cycle Cell Cycle Regulation Cell Differentiation process Cell Nucleus Cell Proliferation Chromatin Chromatin Structure Alteration Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclin A Cyclins Diabetes Mellitus Dimethyl Sulfoxide Dose Drug Combinations EZH2 gene Enzyme Inhibitor Drugs Extended Family FK506 FOXM1 gene Family GCG gene Gene Proteins Genes Genome Goals Harmine Human In Vitro Insulin Insulin-Dependent Diabetes Mellitus Label Link Maintenance Mediating Mediator of activation protein Metabolic syndrome Modeling Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nuclear Pathway interactions Pharmaceutical Preparations Phosphotransferases Polycomb Prediabetes syndrome Refractory Regulation Research Residual state Role Scaffolding Protein Signal Transduction Structure of beta Cell of islet Transforming Growth Factor beta YY1 Transcription Factor analog c-myc Genes cell regeneration genome-wide global health in vivo indexing inhibitor/antagonist insulinoma islet member novel novel strategies receptor regenerative therapy therapeutic target trafficking transcription factor

项目摘要

Summary Types 1 and 2 diabetes result entirely or in part from a reduction in numbers of normally functioning pancreatic beta cells. Residual beta cells are present in most people with diabetes, suggesting that regenerative therapies may be uniquely helpful. Inducing human beta cells to regenerate has proven impossible until recently. This has changed with the discovery by several labs of drugs that inhibit the kinase, DYRK1A, and which induce human beta cells to replicate at “rates”, or more properly, “labeling indices”, of ~2%. Proliferation can be augmented by combining DYRK1A inhibitors with TGF-beta superfamily inhibitors or with GLP1 receptor agonists, generating labeling indices of 5-8%. Although these are exciting advances, they also demonstrate that >90% of human beta cells are recalcitrant to cell cycle entry. The cause of this remarkable refractoriness to proliferation is poorly understood. DYRK1A inhibition alters intracellular trafficking of the NFaT family of transcription factors. In the course of our studies on human insulinomas, we have uncovered a parallel pathway, the DREAM-MMB complex, that also restricts human beta cell proliferation. We show here that the extended family of ~200 canonical DREAM-MMB complex genes and proteins appear to be present in human beta cells, and that DREAM complex is switched from a repressive to a proliferative configuration by DYRK1A inhibition. In addition, we have also observed potential overlapping roles for Trithorax and Polycomb complexes with the DREAM complex in restraining human beta cell proliferation. Accordingly, in this application, we propose three Specific Aims: Aim 1. Complete The Characterization of the Functional DREAM-MMB Complex in the Human Beta Cell. Aim 2. Delineate Candidate DREAM-MMB Complex Target Genes in the Human Beta Cell. Aim 3. Aim 3. Define Genome-Wide Integration of Repressive and Proliferative DREAM-MMB Mediators with Trithorax and Polycomb Chromatin Regulators and DREAM Target Genes in Human Beta Cells. Our overarching goals are: 1) to clearly and comprehensively define the fundamental mechanisms that enforce quiescence in the adult human beta cell; 2) to more clearly elucidate the fundamental mechanisms through which DYRK1A inhibitors, TGFβ inhibitors and GLP1RA’s synergize to induce their remarkable rates of human beta cell proliferation; and 3) to reveal novel pathways and further expand therapeutic targets for human beta cell regeneration for diabetes.

概括类型1和2糖尿病完全或部分原因是正常运作的胰腺数量减少 β细胞。大多数糖尿病患者都存在残留的β细胞，这表明再生疗法可能会有所帮助。直到最近，诱导人β细胞再生才是不可能的。随着几个抑制激酶DyRK1A的药物实验室发现的发现，并且诱导人β细胞以“速率”或更正确的“标记指数”重复约2％。扩散可以通过将DYRK1A抑制剂与TGF-BETA超家族抑制剂或GLP1受体相结合来增强激动剂，产生标签指数为5-8％。尽管这些都是令人兴奋的进步，但他们也证明了 > 90％的人β细胞是细胞周期进入的顽固性。这种出色的耐火性的原因扩散知之甚少。 DYRK1A抑制作用改变了NFAT转录因子家族的细胞内运输。在我们的过程中关于人类胰岛素瘤的研究，我们发现了一个平行的途径，即梦-MMB综合体限制人β细胞增殖。我们在这里表明，大约200个经典的梦想 - 摩尔人的大家庭复杂的基因和蛋白质似乎存在于人的β细胞中，并且该梦络合从反光到通过dyrk1a抑制作用到增殖的构型。另外，我们还观察到 Trithorax和Polycomb复合物的潜在重叠角色与Dream Complex在限制中人β细胞增殖。根据此应用程序，我们提出了三个具体目标：目标1。完成人β细胞中功能性梦-MMB复合物的表征。 AIM2。人类β细胞中的Deleneate候选Dream-MMB复杂靶基因。目标3。目标3。定义全基因组抑制性和繁殖梦想MMB介体的整合在人β细胞中，带有trithorax和polycomb染色质调节剂和梦想靶基因。我们的总体目标是：1）清晰，全面地定义强制执行的基本机制成人人类β细胞中的静止； 2）更清楚地阐明了基本机制 DYRK1A抑制剂，TGFβ抑制剂和GLP1RA的协同作用，以引起其显着的人类速率 β细胞增殖； 3）揭示新的途径并进一步扩大人类beta的治疗靶标糖尿病的细胞再生。