Regulation of beta cell identity and dedifferentiation

β细胞身份和去分化的调节

• 批准号: 10445033
• 负责人: Matthias Hebrok
• 金额: $ 5.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445033
• 关键词: Adult; Affect; Beta Cell; Cell Maintenance; Cell Maturation; Cell physiology; Cells; Cilia; Data; Defect; Deterioration; Development; Diabetes Mellitus; Disease; Duct (organ) structure; Ectopic Expression; Embryo; Endocrine; Event; Failure; Functional disorder; Funding; Gene Expression; Generations; Genetic Transcription; Genomics; Goals; Health; Human; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Lead; Life; Maintenance; Metabolic; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Organ; Organelles; Organism; Pancreas; Pathogenesis; Pathway interactions; Patients; Persons; Physiological; Play; Population; Prediabetes syndrome; Property; Proteins; Regulation; Research; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Model; base; blastomere structure; cell type; cilium biogenesis; data mining; endocrine pancreas development; enhancing factor; experimental study; human stem cells; insight; islet; loss of function; mouse model; novel; novel therapeutic intervention; overexpression; progenitor; stem cells; stressor; transcription factor; treatment strategy

Maintenance of beta cell health has significant implications for Diabetes, both Type 1 and Type 2. Intrinsic changes within the beta cell have an impact on the initiation and progression of these debilitating diseases that require life-long management by the patient. Decades of research has identified the concert of events that must occur to generate a beta cell from embryonic progenitors, primarily using rodent models, and deletion of several of these regulators ablates endocrine, and specifically beta cell, populations. Here, we use a combination of sophisticated transgenic mouse models and human stem cell-derived beta cells to identify critical signals that maintain function in insulin producing cells. The overarching goal of this proposal is to elucidate novel functions of the transcription factor Sox9, currently believed to be only active in pancreas progenitors and adult exocrine duct and centroacinar cells. Similar to another transcription factor, Ngn3, our data indicate that Sox9 is expressed at low levels in mature beta cells where it performs critical functions. The consequences of Sox9 loss are less severe that those observed upon elimination of factors known to result in maturity onset of diabetes in the young (MODY), thus reflecting the reality of human Type 2 Diabetes, in which numerous defects culminate in the development of beta cell dysfunction. We pose that Sox9 plays a central role in regulating essential aspects of beta cell development and function. In the first specific aim, we propose to determine the consequences of Sox9 elimination in mature rodent and human beta cells. Our preliminary data demonstrate that low-level expression of Sox9 supports beta cell properties and loss of the transcription factor promotes beta cell dysfunction. In the second specific aim, we will investigate the consequences of forced Sox9 expression in beta cells with the goal of defining the regulatory network controlled by the transcription factor. We anticipate that mining data from transgenic mice with supra-physiological levels of Sox9 in the beta cells will allow us to assign novel roles to proteins previously not known to influence beta cell function. In the third specific aim, we focus on the mechanisms by which Sox9 modulates beta cell function. Our preliminary data indicate that Sox9 regulates formation and thus function of primary cilia, a cellular organelle known to regulate beta cell activities. In summary, we anticipate that the experiments outlined in this proposal will provide a deeper understanding of regulatory networks that are in place to maintain the appropriate and precise functioning of a beta cell. Uncovering the reasons behind beta cell failure should provide novel insights that can be exploited to devise novel therapeutic strategies for the treatment of patients with Diabetes.

维持 β 细胞健康对 1 型和 2 型糖尿病具有重大影响。β 细胞内的内在变化会影响这些需要患者终生管理的衰弱疾病的发生和进展。数十年的研究已经确定了从胚胎祖细胞产生β细胞所必须发生的一系列事件（主要使用啮齿动物模型），并且删除其中一些调节因子会消除内分泌，特别是β细胞群体。在这里，我们结合使用复杂的转基因小鼠模型和人类干细胞衍生的β细胞来识别维持胰岛素产生细胞功能的关键信号。该提案的首要目标是阐明转录因子 Sox9 的新功能，目前认为该转录因子仅在胰腺祖细胞、成体外分泌管和腺泡中心细胞中具有活性。与另一种转录因子 Ngn3 类似，我们的数据表明 Sox9 在成熟的 β 细胞中低水平表达，并在其中发挥关键功能。 Sox9 缺失的后果不如消除已知导致青少年糖尿病成年发病 (MODY) 的因素后观察到的后果严重，从而反映了人类 2 型糖尿病的现实，其中许多缺陷最终导致 β 细胞功能障碍的发展。我们认为 Sox9 在调节 β 细胞发育和功能的重要方面发挥着核心作用。 在第一个具体目标中，我们建议确定成熟啮齿动物和人类 β 细胞中 Sox9 消除的后果。我们的初步数据表明，Sox9 的低水平表达支持 β 细胞特性，而转录因子的缺失会促进 β 细胞功能障碍。在第二个具体目标中，我们将研究β细胞中强制表达Sox9的后果，目的是定义转录因子控制的调控网络。我们预计，从β细胞中Sox9超生理水平的转基因小鼠中挖掘数据将使我们能够为以前未知的影响β细胞功能的蛋白质分配新的作用。在第三个具体目标中，我们重点关注 Sox9 调节 β 细胞功能的机制。我们的初步数据表明，Sox9 调节初级纤毛的形成和功能，初级纤毛是一种已知调节 β 细胞活性的细胞器。总之，我们预计本提案中概述的实验将提供对维持 β 细胞适当和精确功能的调节网络的更深入理解。揭示β细胞衰竭背后的原因应该提供新的见解，可用于设计治疗糖尿病患者的新治疗策略。

项目成果

Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant.

• DOI: 10.1016/j.stemcr.2017.07.012
• 发表时间: 2017-09-12
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Faleo G;Russ HA;Wisel S;Parent AV;Nguyen V;Nair GG;Freise JE;Villanueva KE;Szot GL;Hebrok M;Tang Q
• 通讯作者: Tang Q

Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation.

• DOI: 10.1038/s42003-021-02818-3
• 发表时间: 2021-11-17
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Heller S;Li Z;Lin Q;Geusz R;Breunig M;Hohwieler M;Zhang X;Nair GG;Seufferlein T;Hebrok M;Sander M;Julier C;Kleger A;Costa IG
• 通讯作者: Costa IG

Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges.

• DOI: 10.1016/j.stem.2018.05.016
• 发表时间: 2018-06-01
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Sneddon JB;Tang Q;Stock P;Bluestone JA;Roy S;Desai T;Hebrok M
• 通讯作者: Hebrok M

Loss of Pancreas upon Activated Wnt Signaling Is Concomitant with Emergence of Gastrointestinal Identity.

激活 Wnt 信号传导后胰腺的丧失伴随着胃肠道特性的出现。

• DOI: 10.1371/journal.pone.0164714
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Muñoz-Bravo,JoseLuis;Flores-Martínez,Alvaro;Herrero-Martin,Griselda;Puri,Sapna;Taketo,MakotoMark;Rojas,Anabel;Hebrok,Matthias;Cano,DavidA
• 通讯作者: Cano,DavidA

Human islets contain four distinct subtypes of β cells.

• DOI: 10.1038/ncomms11756
• 发表时间: 2016-07-11
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Dorrell C;Schug J;Canaday PS;Russ HA;Tarlow BD;Grompe MT;Horton T;Hebrok M;Streeter PR;Kaestner KH;Grompe M
• 通讯作者: Grompe M