DREAM Complex Maintenance of Human Beta Cell Quiescence

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2.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

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.