AN IN VIVO APPROACH TO CELL-BASED THERAPY FOR TYPE I DIABETES

I 型糖尿病细胞疗法的体内方法

• 批准号: 7994507
• 负责人: BEN Z STANGER
• 金额: $ 6.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-11 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994507
• 关键词: Adult; Autoimmune Process; Cell Therapy; Cells; Coupled; Diabetes Mellitus; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Exhibits; Goals; In Vitro; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Methods; Morbidity - disease rate; Obstruction; Pancreas; Pancreatic duct; Patients; Peptides; Phenotype; Population; Rodent; Source; Stem cells; System; Tissues; abstracting; in vivo; islet; small molecule; success

Abstract For patients with type 1 diabetes mellitus (T1DM), the greatest prospect for reduced morbidity and insulin independence is the replacement of ¿-cells coupled with suppression of the underlying autoimmune process. Since the initially dramatic successes of islet transplantation in achieving this goal with donor islets, significant efforts have been directed at identifying and expanding alternate sources of ¿-cells. These efforts have been hampered by several challenges: adult ¿-cells are mainly derived by the replication of existing ¿-cells, non-¿-cells give rise to ¿-cells with low efficiency, and the ¿-cell phenotype is difficult to achieve or maintain in vitro. In tissues that maintain mass by replication of existing cells, certain forms of injury result in the emergence of a normally quiescent progenitor cell population ("facultative stem cells"). Previous studies have pointed to the presence of such a population in the adult pancreas, but findings have been inconsistent and the precursor population has been elusive. This proposal builds on convincing recent evidence that facultative stem cells reside within the pancreatic ducts and can give rise to large numbers of ¿-cells following a specific form of injury: obstruction of the pancreatic duct. This proposal seeks to identify the ductal cells that exhibit this potential, and to develop practical methods for the efficient initiation of duct-to-islet conversion in vitro or in vivo. Specifically, our goal is to stimulate duct- to-islet conversion in rodents with established diabetes as a proof-of-principle for this approach. The proposed studies have the potential for a major impact on the treatment of T1DM by promoting ¿-cells neogenesis through the introduction of peptides or small molecules into the pancreatic ductal system.

摘要 对于1型糖尿病（T1 DM）患者，降低发病率的最大前景 而胰岛素依赖性是替代胰岛细胞，同时抑制潜在的 自身免疫过程由于胰岛移植在实现这一目标方面最初取得了巨大的成功， 目标与捐助胰岛，重大努力已被定向在确定和扩大替代 细胞的来源。这些努力受到了几个挑战的阻碍：成人细胞主要是 由现有的<$-细胞复制而来，非<$-细胞以低效率产生<$-细胞， 在体外很难达到或维持细胞表型。 在通过复制现有细胞来维持质量的组织中，某些形式的损伤会导致 正常静止的祖细胞群（“兼性干细胞”）的出现。以前的研究 已经指出在成人胰腺中存在这样的群体，但是研究结果已经被证明是不可能的。 不一致，前体人口一直难以捉摸。这一建议建立在令人信服的最近 有证据表明，兼性干细胞存在于胰腺导管内， 特定形式的损伤后的细胞数量：胰管阻塞。这项建议 试图识别表现出这种潜力的导管细胞，并开发出实用的方法， 在体外或体内有效启动导管-胰岛转化。我们的目标是刺激导管- 在患有糖尿病的啮齿动物中的胰岛转化作为该方法的原理证明。的 拟议的研究有可能通过促进β-细胞对T1 DM的治疗产生重大影响， 通过将肽或小分子引入胰腺导管系统的新生。