MODEL B CELLS FOR USE IN DIABETES TREATMENT

用于糖尿病治疗的 B 型细胞

• 批准号: 2377810
• 负责人: IOANNIS CONSTANTINIDIS
• 金额: $ 10.81万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377810
• 关键词: alginates; artificial endocrine pancreas; bioenergetics; blood glucose; brain metabolism; disease /disorder model; glycosuria; hypoxia; laboratory rat; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; pancreatic islets; streptozotocin; tissue /cell culture; tissue engineering

Transplantation of islets or Beta-cells offers a realistic possibility for physiological control of blood glucose in diabetics. All reports agree that euglycemia can be achieved for a limited time period (less than 1 year) following transplantation. A major limitation to using normal islets or Beta-cells in implantable bioartificial pancreata is availability. Normal cells isolated from mammalian glands exhibit littl growth, and rapidly lose their differentiated properties in culture. With an estimated 300,000 cases of insulin dependent diabetes mellitus and an additional 30,000 new cases per year in the USA, alone, the deman for islets would be enormous. Consequently, cell lines which retain in culture the differentiated properties of normal islets in vivo are neede for the development of a bioartificial pancreas. Since all living systems need energy to sustain their life and function, knowledge about their energy metabolism as it responds to expected physiologic changes is crucial in assessing the viability and function of these bioartificia devices. In this application, we propose to study the bioenergetic stability of the continuous Beta cell line, BetaTC3, in an immunoprotected environment under repetitive glucose stimulations and hypoxic stresses. Furthermore, we will implant immunoprotected BetaTC3 cells in streptozotocin-induced diabetic rats, and investigate their ability to restore glucose regulation in these animals. This type of information is currently unavailable, and will add greatly to the understanding of the capabilities and limitations of an implantable bioartificial pancreas. We propose to use the non-invasive modality of Nuclear Magnetic Resonance spectroscopy, for both in vitro and in vivo studies. 31P NMR will assess intracellular levels of high and low energ phosphates, and 13C NMR will determine the relative fluxes through glycolysis and the tricarboxylic acid cycle. Enzymatic assays of the perfusion medium effluent, perchloric acid extract of the cells, and histologic examinations of the beads will be performed in support of the in vitro studies. Changes in tissue biochemistry and key physiological parameters including blood glucose and insulin levels will be monitored to assess the success of the implant. This proposal is the beginning of an interdisciplinary project that has brought together expertise from engineering, chemistry, physics and medicine. Our long range goal is to develop a clinically useful implantable bioartificial pancreas for the treatment of diabetes mellitu in human patients.

胰岛或β细胞的移植提供了现实的可能性 用于糖尿病患者血糖的生理控制。 所有报告 同意欧盟可以在有限的时间内实现（少于 移植后1年以上。 使用的一个主要限制是 植入式生物人工胰腺中的正常胰岛或β细胞， 空房的 从哺乳动物腺体中分离的正常细胞几乎不表现出 生长，并在培养中迅速失去其分化特性。 估计有30万例胰岛素依赖型糖尿病 仅在美国，每年就有30，000例新病例， 岛屿的数量将是巨大的 因此，保留在 需要在体内培养正常胰岛的分化特性， 用于开发生物人工胰腺。 因为所有活着的人 系统需要能量来维持其生命和功能， 他们的能量代谢，因为它响应预期的生理变化 在评估这些生物人工器官的可行性和功能方面是至关重要的， 装置. 在这个应用中，我们建议研究生物能 连续β细胞系BetaTC 3在 在重复葡萄糖刺激下的免疫保护环境， 低氧应激 此外，我们将植入免疫保护的BetaTC3 细胞在链脲佐菌素诱导的糖尿病大鼠，并探讨其 恢复这些动物的葡萄糖调节能力。 这种类型的 信息目前不可用，将大大增加 了解可植入式植入物的能力和局限性， 生物人工胰腺 我们建议使用非侵入性的方式， 核磁共振光谱，用于体外和体内 问题研究 31P NMR将评估细胞内高能和低能 磷酸盐，和13 C NMR将确定相对通量通过 糖酵解和三羧酸循环。 的酶促测定 灌注培养基流出物、细胞的高氯酸提取物，以及 将对珠子进行组织学检查，以支持 体外研究。 组织生物化学和关键生理 将监测包括血糖和胰岛素水平在内的参数 来评估植入的成功率 该提案是一个跨学科项目的开始， 汇集了来自工程、化学、物理和 药 我们的长期目标是开发一种临床上有用的 植入式生物人工胰腺治疗糖尿病 在人类病人身上。