DREAM Complex Maintenance of Human Beta Cell Quiescence

DREAM 复合物维持人类 β 细胞静止

• 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
• 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

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.

摘要 1型和2型糖尿病的全部或部分原因是正常胰腺功能的数量减少。 β细胞。在大多数糖尿病患者中都存在残留的β细胞，这表明再生疗法 可能会有独一无二的帮助。直到最近，诱导人β细胞再生一直被证明是不可能的。这 随着几个实验室发现了抑制激酶DYRK1A的药物，并诱导 人类β细胞以~2%的“速率”复制，或者更确切地说，是“标记指数”。扩散可以是 通过将DYRK1A抑制剂与转化生长因子-β超家族抑制剂或与GLP1受体结合而增强 激动剂，产生5-8%的标记指数。尽管这些都是令人兴奋的进步，但它们也证明了 90%的人类β细胞不能进入细胞周期。这一惊人的不可抗拒的原因 对核扩散的了解甚少。 抑制DYRK1A改变NFAT转录因子家族的细胞内运输。在我们的过程中 在对人类胰岛素瘤的研究中，我们发现了一条平行的途径，即梦想-MMB复合体，这也是 限制人类β细胞的增殖。我们在这里展示了~200个经典梦想-MMB的大家庭 人类β细胞中似乎存在复杂的基因和蛋白质，而梦境复合体发生了转换 通过抑制DYRK1A，从抑制性构型转变为增殖性构型。此外，我们还观察到 三胸和多梳复合体与梦境复合体在抑制中的潜在重叠作用 人类β细胞的增殖。因此，在本申请中，我们提出了三个具体目标： 目的1.完成人Beta细胞中功能性DREAM-MMB复合体的鉴定。 目的2.在人Beta细胞中筛选DREAM-MMB复合靶基因。 目标3.目标3.定义抑制性和增殖性梦境-MMB介体的全基因组整合 在人类Beta细胞中使用三胸和多梳染色质调节剂和梦想靶基因。 我们的总体目标是：1)明确和全面地界定执行 成人β细胞中的静息；2)更清楚地阐明通过 DYRK1a抑制剂、转化生长因子β抑制剂和GLP1RA的协同作用诱导其对人 β细胞增殖；以及3)揭示人类β细胞的新途径和进一步扩大治疗靶点 糖尿病的细胞再生。