Identifying Physiological and Molecular Inducers of Beta Cell Maturation

识别 β 细胞成熟的生理和分子诱导剂

• 批准号: 9038361
• 负责人: Philip Thomas Pauerstein
• 金额: $ 3.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038361
• 关键词: Adult; Affect; Beta Cell; Biological Assay; Birth; Blood Glucose; Bypass; Calcineurin; Calcium; Cardiac Myocytes; Cell Count; Cell Maturation; Cell Nucleus; Cell Proliferation; Cell Transplantation; Cell membrane; Cell physiology; Cells; Development; Diabetes Mellitus; Disease; Electric Stimulation; Environment; Exocytosis; Exposure to; Gene Expression; Generations; Genes; Glucose; Health; In Vitro; Insulin; Islets of Langerhans; Label; Life; Light; Methods; Molecular; Neonatal; Neurons; Phosphotransferases; Physiological; Process; Proteins; Regulation; Replacement Therapy; Schedule; Signal Pathway; Signal Transduction; Source; Stimulus; Testing; Therapeutic; Transgenic Organisms; Transplantation; United States; Vesicle; Viral; base; blood glucose regulation; cell type; diabetes mellitus therapy; fetal; glucose uptake; improved; in vivo; islet; microbial; nuclear factors of activated T-cells; optogenetics; postnatal; prevent; tool; transcription factor

DESCRIPTION (provided by applicant): Diabetes mellitus is a disease of disordered regulation of blood sugar, affecting over eight percent of people in the United States. In diabetes, the insulin-producing beta cells of the pancreatic islets are unable to properly maintain normal blood glucose levels because of either insufficient beta cell number or insufficient beta cell function. Treating diabetes by replacing islets has been proposed as a therapeutic strategy, but transplantable material is limited. Understanding how to produce functional beta cells from alternate sources could bypass this limitation and enable islet replacement therapies. Current methods for in vitro generation of beta cells produce cells that express insulin, but that resembles fetal or neonatal beta cells with limited glucose-regulating capacity. This project will investigate the physiological and molecular signals that normally induce islets to transition from an immature less-functional state to a mature cell type capable of effective blood glucose regulation. To achieve this, we will first test whether mimicking normal glucose-induced cell depolarization by experimentally inducing scheduled electrical activity in cultured islets is sufficient to convert immature postnatal beta cells into mature and fully functional beta cells. Electrical activity will be controlled by expressing optogenetic proteins specifically in beta cell, which will produce an electrical current across the cell membrane when cells are exposed to a specific wavelength of light. Second, we will test whether activating the Calcineurin/NFAT signaling pathway, which senses cellular calcium levels and normally controls beta cell proliferation and function, is sufficient to promote maturation of cultured immature islets. These studies will reveal cellular and molecular stimuli that control how islets normally acquire functio during development, and will inform efforts at generating new functional beta cells from renewable sources.

描述（由申请人提供）：糖尿病是一种血糖调节紊乱的疾病，在美国影响着超过8%的人。在糖尿病中，胰岛分泌胰岛素的β细胞无法正常维持

项目成果

A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis.

由信号蛋白到神经毡蛋白信号传导定义的径向轴控制胰岛形态发生。

• DOI: 10.1242/dev.148684
• 发表时间: 2017
• 期刊: Development (Cambridge, England)
• 作者: Pauerstein,PhilipT;Tellez,Krissie;Willmarth,KirkB;Park,KeonMin;Hsueh,Brian;EfsunArda,H;Gu,Xueying;Aghajanian,Haig;Deisseroth,Karl;Epstein,JonathanA;Kim,SeungK
• 通讯作者: Kim,SeungK