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Mechanisms of beta cell maturation

β细胞成熟的机制

基本信息

批准号：
9301541
负责人：
Anil Bhushan
金额：
$ 58.96万
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：
2015-09-30 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301541
关键词：
Adult Affect Alpha Cell Beta Cell Biochemical Birth Blood Blood Glucose Cell Differentiation process Cell Maturation Cell Therapy Cell physiology Cells Data Diabetes Mellitus Embryo Endemic Diseases Enzymes Epigenetic Process FRAP1 gene Gene Combinations Gene Expression Genes Genetic Glucose Goals HIF1A gene Human Hypoxia Impairment In Vitro Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Knowledge Life Mediating Metabolic Metabolism Molecular Mus Neonatal Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathway interactions Patients Play Population Process Protocols documentation Regulation Rodent Role Signal Pathway Signal Transduction Source Stem cells Techniques Therapeutic Uses Transgenic Mice VHL protein Work blood glucose regulation diabetic patient embryonic stem cell gain of function genetic manipulation human embryonic stem cell human stem cells in vivo insulin secretion mouse model novel programs public health relevance small molecule standard of care stem cell biology stem cell population transcription factor

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus has become an endemic disease that afflicts close to 29 million patients in the US. One of the underlying causes of diabetes is the impaired function or loss of insulin-producing beta cells that reside within the pancreas. As a consequence, patients suffering from either type 1 or type 2 diabetes have to rely on exogenous injections of insulin to regulate their blood sugar levels. Recent advances in stem cell biology are now making it likely that it will be possible to generate functional insulin-producing cells frm human stem cells, thus producing a renewable source of cells that could be used for therapeutic purposes to restore normal blood sugar levels. However, while dramatic advances have been made in the recent past, the current beta cells derived from stem cells are not fully matured and thus not fully functional. In this proposal, we describe preliminary studies indicating that programing of cellular metabolism plays an important role during the maturation of beta cells after birth. We demonstrate that mTOR signaling and its downstream components regulated by the transcription factor Hif1α regulate critical aspects of cellular metabolism during functional maturation of beta cells. The focus of this proposal is to define the roles of the mTOR and Hif1α signaling during the neonatal process of beta cell maturation in rodent and humans. We are proposing three specific aims using a combination of sophisticated transgenic mouse models and immature human beta-like cells we have generated from human embryonic stem cells. Our studies will define the role and relationships between the mTOR and Hif1α signaling cascades during rodent and human beta cell maturation. The overarching goal is to define the signals that guide this process with the intent of manipulating them to generate fully matured and functional human beta cells from stem cells. We envision that these efforts will provide novel and important information that can accelerate cell therapy approaches for the treatment of diabetic patients.

描述（由申请人提供）：糖尿病已成为一种地方病，在美国困扰着近2900万患者。糖尿病的根本原因之一是胰腺内产生胰岛素的β细胞的功能受损或丧失。作为因此，患有1型或2型糖尿病的患者不得不依赖外源性胰岛素注射来调节他们的血糖水平。干细胞生物学的最新进展使得从人类干细胞中产生功能性胰岛素产生细胞成为可能，从而产生可用于治疗目的的可再生细胞来源，以恢复正常的血糖水平。然而，虽然最近取得了巨大的进展，但目前来源于干细胞的β细胞尚未完全成熟，因此功能不全。在这个提议中，我们描述了初步研究表明，细胞代谢的编程在出生后β细胞的成熟过程中起着重要作用。我们证明了mTOR信号传导及其下游成分由转录因子Hif1α调节，调节β细胞功能成熟过程中细胞代谢的关键方面。该提案的重点是确定mTOR和Hif1α信号在啮齿动物和人类β细胞成熟的新生过程中的作用。我们提出了三个具体的目标，使用复杂的转基因小鼠模型和我们从人类胚胎干细胞中产生的不成熟的人类β样细胞的组合。我们的研究将确定mTOR和Hif1α信号级联在啮齿动物和人类β细胞成熟过程中的作用和关系。总体目标是定义引导这一过程的信号，目的是操纵它们从干细胞产生完全成熟和功能性的人类β细胞。我们设想，这些努力将提供新的和重要的信息，可以加速细胞治疗方法治疗糖尿病患者。