Signaling and Epigenetic Control of Beta Cell Development and Regeneration

β 细胞发育和再生的信号传导和表观遗传控制

• 批准号: 7994316
• 负责人: Kenneth Zaret
• 金额: $ 81.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994316
• 关键词: Acute; Adult; Agonist; Beta Cell; Cell Differentiation process; Cells; Cellular biology; Chromatin; Clinical Trials; Complex; Cues; Development; Diabetes Mellitus; Duct (organ) structure; Embryo; Embryonic Development; Endocrine; Endoderm Cell; Enzymes; Epigenetic Process; Epithelium; Generations; Genetic; Goals; Growth; Helper-Inducer T-Lymphocyte; Human; Information Technology; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Mediating; Modification; Natural regeneration; Pancreas; Pancreatic Injury; Pathway interactions; Population; Research; Research Personnel; Resort; Rodent; Running; Signal Pathway; Signal Transduction; Source; Stem cells; Testing; Tissues; Translating; Undifferentiated; Work; cell type; chromatin modification; embryonic stem cell; endocrine pancreas development; enzyme activity; extracellular; fetal; fetus cell; human embryonic stem cell; inhibitor/antagonist; injured; novel; progenitor; public health relevance; regenerative; response; small molecule; transcription factor; type I diabetic

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.

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永久β细胞形成的信号传导和表观遗传线索，并促进β细胞生物学联盟（BCBC）中此类进展的应用，以改善I型糖尿病（T1D）。迄今为止，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而动态的信号网络，它从未分化的内胚层细胞诱导PDX 1+胰腺祖细胞，以及成人组织中可以从非β细胞产生β细胞的条件。然而，诱导PDX 1+胰腺祖细胞在胚胎中产生NGN 3+内分泌祖细胞的细胞外信号的特定组合，诱导NGN 3+细胞产生永久胰岛素+ β细胞的信号，以及诱导成体再生中非β细胞形成新β细胞的信号，仍有待确定。此外，很少有人知道染色质修饰，使路径的β细胞。我们注意到细胞分化的细胞外诱导物通常是可溶性分子，对这些诱导物的细胞反应途径通常由酶介导，并且许多由此产生的染色质修饰通常由酶介导。因此，我们计划鉴定促进内分泌和β细胞分化和再生所必需的信号和染色质转换，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β细胞的形成和生长，而不必求助于遗传修饰。为了给该领域提供新的方向，我们的主要重点是以前未被重视的信号和反应机制以及新型β细胞祖细胞。通过在BCBC联盟内分享我们工作的技术和信息，研究从人类胚胎干细胞产生β细胞的合作者，整个领域，以及运行T1D临床试验的卓越中心，我们的研究将被转化为帮助治愈糖尿病。 公共卫生相关性：我们强调识别促进胰腺祖细胞发育为β细胞的非预期信号和表观遗传学线索，旨在为该领域提供新的方向，以从胚胎干细胞和从损伤胰腺中产生的新细胞来源产生I型糖尿病患者的β细胞，而不必求助于细胞的遗传修饰。