Regulation of beta cell identity and dedifferentiation

β细胞身份和去分化的调节

基本信息

批准号：
10013206
负责人：
Matthias Hebrok
金额：
$ 41.52万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013206
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 Physiological Play Population Prediabetes syndrome Property Proteins Regulation Research Rodent Rodent Model Role Signal Pathway Signal Transduction Structure 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 therapeutics overexpression progenitor stem cells stressor transcription factor treatment strategy

项目摘要

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.

β细胞健康的维持对糖尿病（型1型和2型）都具有重大影响。β细胞内的内在变化对这些衰弱的疾病的起始和进展有影响，这些疾病需要患者终身管理。数十年的研究已经确定了从胚胎祖细胞产生β细胞（主要使用啮齿动物模型）的事件的音乐会，并删除了这些调节剂中的几种内分泌，尤其是β细胞种群。在这里，我们结合了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。该提案的总体目标是阐明转录因子SOX9的新功能，该功能目前仅在胰腺祖细胞中活跃，成人外分泌导管和质心细胞。与另一个转录因子NGN3相似，我们的数据表明，在成熟的β单元中，SOX9在执行关键功能的成熟β细胞中表达。 SOX9损失的后果不那么严重，以至于消除已知因素导致年轻人（Mody）成熟的因素开始，从而反映了人类2型糖尿病的现实，其中许多缺陷在β细胞功能障碍的发展中达到了最终形式。我们构成Sox9在调节β细胞开发和功能的基本方面起着核心作用。在第一个特定目的中，我们建议确定成熟啮齿动物和人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，转录因子的丢失促进了β细胞功能障碍。在第二个特定目标中，我们将研究β细胞中强制SOX9表达的后果，以定义由转录因子控制的调节网络。我们预计，来自β细胞中SOX9的转基因小鼠的采矿数据将使我们能够将新作用分配给以前未知会影响β细胞功能的蛋白质。在第三个特定目的中，我们专注于Sox9调节β细胞功能的机制。我们的初步数据表明，Sox9调节了原发性纤毛的形成，从而调节了一种细胞细胞器，该细胞细胞器已知可调节β细胞活性。总而言之，我们预计该提案中概述的实验将对维持Beta细胞的适当和精确功能的监管网络有更深入的了解。揭示β细胞衰竭背后的原因应提供新颖的见解，这些见解可以被利用，以设计新的治疗策略来治疗糖尿病患者。