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产生大量且可再生的人类胰岛素产生β细胞进行替代疗法。另一个是了解如何通过内源性残留β细胞来实现替代或补充。一种有吸引力且可探讨的方法是诱导人β细胞复制，以便从内源性来源，尸体胰岛或其他其他来源（例如各种类型的干细胞或重编程细胞）得出的成熟的，分化的人β细胞可能会扩展到能够治疗大量糖尿病患者的人数。尽管常规的教条和广泛的经验表明，成年人类β细胞是最终区分并且无法复制的，但本应用程序中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，该组表明：a）可以诱导人β细胞快速复制并仍然保留其分化的功能性表型：和，b）许多直接和间接的，上游，上游上游的人类beta细胞周期活化存在。该应用的目标是组装一群高级科学家，他们专注于人类β细胞生物学和治疗的各个方面，以促进和加快人类β细胞复制，分化和替代策略，并与Beta细胞生物学财团（BCBC）的其他成员分享这一专业知识。具体目的是：1）充分定义人类β细胞中G1/S细胞周期分子的正常生理学，作用机理，治疗功效和安全性。 2）探索G1/s检查点上游的调节途径，以定义β细胞特定途径以激活人β细胞的增殖。 3）与其他BCBC研究人员共享知识，数据，试剂，动物，技术和技术。数据中已经表明，有许多新颖的方法可以诱导人β细胞复制，并且额外的重点和精致应有助于将这些方法从实验室基准研究转变为人类糖尿病治疗。 公共卫生相关性：糖尿病会影响约2700万美国人，并导致β细胞数量和功能不足。调查团队开发了新的方法，使用内源性细胞周期控制分子诱导健壮的人β细胞复制。本应用的目标是精确定义这些分子及其上游调节器的工作方式，这是最适合治疗努力的方法，以及如何将这些知识转移到实用的临床范例中。