Signaling and Epigenetic Control of Beta Cell Development and Regeneration

描述（由申请人提供）：本提案的目标是发现在胚胎发育和成人再生环境中指导内分泌细胞祖细胞和终β细胞形成的信号和表观遗传线索，并促进β细胞生物学联盟（BCBC）将这些进展应用于改善I型糖尿病（T1D）。迄今为止，在β细胞发育领域的大多数研究都集中在转录因子上。我们实验室最近的研究揭示了一个复杂的、动态的信号网络，可以从未分化的内胚层细胞诱导PDX1+胰腺祖细胞，以及在成人组织中非β细胞可以产生β细胞的条件。然而，在胚胎中诱导PDX1+胰腺祖细胞生成NGN3+内分泌祖细胞的细胞外信号、诱导NGN3+细胞生成最终的胰岛素+ β细胞的信号以及诱导非β细胞在成人再生中形成新的β细胞的信号的具体组合仍有待确定。此外，对于染色质修饰使通往β细胞的途径知之甚少。我们注意到细胞分化的细胞外诱导剂通常是可溶性分子，细胞对这些诱导剂的反应途径通常是由酶介导的，并且许多染色质的修饰通常是由酶介导的。因此，我们计划识别促进内分泌和β细胞分化和再生所必需的信号和染色质转变，这将允许使用酶活性的小分子修饰剂来调节干细胞和其他祖细胞的形成和生长，而不必诉诸基因修饰。为了为该领域提供新的方向，我们的主要重点是以前未被认识的信号和反应机制以及新型β细胞祖细胞。通过与BCBC联盟、研究人类胚胎干细胞生成β细胞的合作者、整个领域以及开展T1D临床试验的卓越中心分享我们的技术和信息，我们的研究将转化为帮助治疗糖尿病。

DESCRIPTION (provided by applicant): The goal of this proposal is to discover signaling and epigenetic cues that direct the formation of endocrine cell progenitors and definitive beta cells in embryonic development and adult regenerative contexts, and to promote the application of such advances within the Beta Cell Biology Consortium (BCBC) to ameliorate type I diabetes (T1D). To date, most research in the beta cell development field has focused on transcription factors. Recent studies from our laboratories have revealed a complex and dynamic network of signals that induce PDX1+ pancreatic progenitors from undifferentiated endoderm cells, as well as conditions in adult tissues in which beta cells can be generated from non-beta cells. Yet the specific combination of extracellular cues that induce PDX1+ pancreatic progenitors to make NGN3+ endocrine progenitors in the embryo, the cues that induce NGN3+ cells to make definitive insulin+ beta cells, and the cues that induce the formation of new beta cells from non-beta cells in adult regeneration, remain to be defined. In addition, little is known about the chromatin modifications that enable the paths to the beta cell. We note that the extracellular inducers of cell differentiation usually are soluble molecules, that the cellular response pathways to such inducers usually are mediated by enzymes, and that many of the resulting modifications of chromatin usually are mediated by enzymes. Thus our plan to identify signals and chromatin transitions necessary to promote endocrine and beta cell differentiation and regeneration will allow the use of small molecule modifiers of enzyme activity to modulate the formation and growth of beta cells from stem cells and other progenitors, without having to resort to genetic modification. To provide novel directions for the field, our primary emphasis is on previously unappreciated signals and response mechanisms and new types of beta cell progenitors. By sharing technology and information from our work within the BCBC consortium, collaborators investigating the generation of beta cells from human embryonic stem cells, the field at large, and centers of excellence running clinical trials for T1D, our studies will be translated to help cure diabetes. PUBLIC HEALTH RELEVANCE: Our emphasis on identifying unanticipated signals and epigenetic cues that promote the development of pancreatic progenitors to beta cells is intended to provide novel directions for the field to generate beta cells for type I diabetics from embryonic stem cells and from new cell sources that arise in the injured pancreas, without having to resort to genetic modification of the cells.