Multi-Disciplinary Approaches to Driving Therapeutic Human Beta Cell Replication

驱动治疗性人类β细胞复制的多学科方法

• 批准号: 8144434
• 负责人: ANDREW F. STEWART
• 金额: $ 87.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144434
• 关键词: Adult; Affect; American; Animals; Automobile Driving; Beta Cell; Cadaver; Cell Count; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Therapy; Cell physiology; Cells; Cellular biology; Clinical; Data; Diabetes Mellitus; Goals; Hand; Human; Insulin; Islets of Langerhans; Knowledge; Laboratories; Pathway interactions; Patients; Phenotype; Physiology; Reagent; Regulatory Pathway; Replacement Therapy; Research; Research Personnel; Residual state; Safety; Senior Scientist; Source; Stem cells; Therapeutic; Treatment Efficacy; Work; beta cell replacement; diabetes mellitus therapy; experience; member; novel; public health relevance; technology/technique

DESCRIPTION (provided by applicant): One of the principal goals of diabetes research is to generate a large and renewable supply of human insulin-producing beta cells for replacement therapy. Another is to understand how replacement or replenishment might be accomplished from endogenous, residual beta cells. One attractive and tractable approach is the induction of human beta cell replication, so that mature, differentiated human beta cells derived from endogenous sources, from cadaver pancreatic islets, or from the other sources (such as various types of stem cells or reprogrammed cells), might be expanded to numbers capable of treating large numbers of patients with diabetes. Whereas conventional dogma and widespread experience has suggested that adult human beta cells are terminally differentiated and cannot replicate, the investigators in this application have recently shown that this is not completely true. By manipulating cell cycle control, specifically the G1/S control checkpoint of the cell cycle, this group has shown that: a) human beta cells can be induced to replicate rapidly and still retain their differentiated, functional phenotype: and, b) that many direct and indirect, upstream options for human beta cell cycle activation exist. The goals of this application are to assemble a group of senior scientists who focus on all aspects of human beta cell biology and therapy, to facilitate and expedite human beta cell replication, differentiation and replacement strategies, and to share this expertise with the other members of the Beta Cell Biology Consortium (BCBC). The Specific Aims are: 1) To Fully Define The Normal Physiology, Mechanisms of Action, Therapeutic Efficacy and Safety of G1/S Cell Cycle Molecules In The Human Beta Cell. 2) To Explore the Regulatory Pathways Upstream Of The G1/S Checkpoint To Define Beta-Cell Specific Pathways To Activate Proliferation in Human Beta Cells. 3) To Share Knowledge, Data, Reagents, Animals, Technologies, and Techniques with Other BCBC Investigators. Data already in hand indicates that there are many novel ways to induce human beta cell replication, and that additional focus and refinement should help transform these approaches from laboratory bench research to human diabetes therapy. PUBLIC HEALTH RELEVANCE: Diabetes affects some 27 million Americans, and results from deficient beta cell numbers and function. The investigative team has developed novel ways to induce robust human beta cell replication using endogenous cell cycle control molecules. The goals of this application are to define precisely how these molecules and their upstream regulators work, which are the best for therapeutic efforts, and how to transfer this knowledge to practical clinical paradigms.

描述(由申请人提供)：糖尿病研究的主要目标之一是为替代疗法产生大量可再生的人类胰岛素分泌β细胞。另一个是了解内源性残留的β细胞是如何完成替代或补充的。一种有吸引力和易操作的方法是诱导人类β细胞复制，这样来自内源性来源、身体胰岛或其他来源(如各种类型的干细胞或重新编程的细胞)的成熟、分化的人类β细胞可能会扩大到能够治疗大量糖尿病患者的数量。虽然传统的教条和广泛的经验表明，成年人的β细胞是终末分化的，不能复制，但这一应用的研究人员最近表明，这并不完全正确。通过操纵细胞周期控制，特别是细胞周期的G1/S控制检查点，该小组已经证明：a)可以诱导人类β细胞快速复制，并且仍然保持其分化的、功能表型：以及，b)存在许多直接和间接的上游选择来激活人类β细胞周期。该应用程序的目标是聚集一群专注于人类β细胞生物学和治疗的所有方面的资深科学家，促进和加快人类β细胞复制、分化和替换策略，并与Beta细胞生物学联盟(BCBC)的其他成员分享这一专业知识。具体目标是：1)全面明确G1/S细胞周期分子在人Beta细胞中的正常生理、作用机制、治疗效果和安全性。2)探索G1/S检查点上游的调控途径，确定激活人β细胞增殖的β细胞特异性途径。3)与其他BCBC调查人员分享知识、数据、试剂、动物、技术和技术。已有的数据表明，有许多诱导人类β细胞复制的新方法，额外的关注和改进应该有助于将这些方法从实验室台架研究转变为人类糖尿病治疗。 与公共健康相关：糖尿病影响了大约2700万美国人，是由于β细胞数量和功能不足造成的。研究小组开发了使用内源性细胞周期控制分子诱导强大的人类β细胞复制的新方法。这项应用的目标是准确地定义这些分子及其上游调节因子是如何工作的，哪些是最适合治疗努力的，以及如何将这些知识转化为实际的临床范例。