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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.

总结 1型和2型糖尿病完全或部分地由正常功能的胰腺癌细胞数量减少引起。 β细胞大多数糖尿病患者体内都存在残余的β细胞，这表明再生疗法可能是唯一有帮助的。诱导人类β细胞再生直到最近才被证明是不可能的。这随着几个实验室发现抑制激酶DYRK 1A的药物，人类β细胞以约2%的“速率”，或更恰当地说，“标记指数”复制。增殖可通过将DYRK 1A抑制剂与TGF-β超家族抑制剂或与GLP 1受体组合来增强激动剂，产生5- 8%的标记指数。虽然这些都是令人兴奋的进步，但它们也表明，超过90%的人类β细胞都不愿意进入细胞周期。造成这种显著的顽固性的原因对扩散的了解很少。 DYRK 1A抑制改变转录因子的NFaT家族的细胞内运输。在我们的在对人类胰岛素瘤的研究中，我们发现了一个平行的途径，DREAM-MMB复合物，限制人类β细胞增殖。我们在这里表明，约200个典型的DREAM-MMB的大家庭，复杂的基因和蛋白质似乎存在于人类β细胞中，并且DREAM复合物被转换为通过DYRK 1A抑制从抑制性构型转变为增殖性构型。此外，我们还观察到， Trithorax和Polycomb复合物与DREAM复合物在抑制人β细胞增殖。因此，在本申请中，我们提出三个具体目的：目标1.完成人类β细胞中功能性DREAM-MMB复合物的表征。目标二。描述人类β细胞中的候选DREAM-MMB复合物靶基因。目标3.目标3。定义抑制性和破坏性DREAM-MMB介导因子的全基因组整合与三胸和多梳染色质调节剂和DREAM靶基因在人类β细胞。我们的总体目标是：1）明确和全面地界定执行《公约》的基本机制，静止在成年人β细胞; 2）更清楚地阐明的基本机制，其中DYRK 1A抑制剂、TGFβ抑制剂和GLP 1 RA的协同作用诱导其显著的人肿瘤发生率。 β细胞增殖;和3）揭示新的途径并进一步扩大人β细胞增殖的治疗靶点。糖尿病的细胞再生