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: 8717474
• 负责人: Philip Thomas Pauerstein
• 金额: $ 3.29万
• 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/8717474
• 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; 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; public health relevance; tool; transcription factor

Project Summary 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 resemble 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 cells, 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 function during development, and will inform efforts at generating new functional beta cells from renewable sources.

项目摘要 糖尿病是一种血糖调节紊乱的疾病， 美国的在糖尿病中，胰岛中产生胰岛素的β细胞不能正常分泌胰岛素， 维持正常的血糖水平，因为β细胞数量不足或β细胞 功能通过替代胰岛治疗糖尿病已被提出作为一种治疗策略，但可移植 材料有限。了解如何从替代来源产生功能性β细胞可以绕过 这一限制并使胰岛替代疗法成为可能。目前体外产生β细胞的方法 产生表达胰岛素的细胞，但类似于葡萄糖调节有限的胎儿或新生儿β细胞 容量本项目将研究正常情况下诱导胰岛生长的生理和分子信号， 从不成熟的低功能状态转变为能够有效控制血糖的成熟细胞类型 调控为了实现这一目标，我们将首先测试是否通过以下方式模拟正常葡萄糖诱导的细胞去极化 在培养的胰岛中通过实验诱导预定的电活动足以将出生后未成熟的胰岛转化为 将β细胞转化为成熟的功能齐全的β细胞。电活动将通过表达 光遗传蛋白，特别是在β细胞，这将产生一个电流通过细胞膜 当细胞暴露于特定波长的光时。其次，我们将测试是否激活 钙调神经磷酸酶/NFAT信号通路，感知细胞钙水平并正常控制β细胞 增殖和功能，足以促进培养的未成熟胰岛的成熟。这些研究将 揭示控制胰岛在发育过程中如何正常获得功能的细胞和分子刺激， 将为从可再生资源中产生新的功能性β细胞的努力提供信息。