The Role of Adenosine Kinase in Controlling Beta-Cell Regeneration

 描述(申请人提供)：近几十年来，糖尿病的患病率出现了惊人的增长。这种疾病越来越频繁地威胁着我们社会的健康，并使人们注意到目前缺乏适当的预防和治疗办法。虽然寻求多种治疗策略很重要，但利用胰岛细胞的再生能力来增加个体的胰岛素分泌能力是有希望的方法之一。最近，以发现为导向的无偏化学筛选导致代谢酶腺苷激酶(ADK)被鉴定为啮齿动物和猪？细胞复制的调节因子。重要的是，在体外和体内，小分子ADK抑制剂选择性地刺激细胞的复制，但不能刺激α细胞的复制。ADK作为细胞再生调节因子的研究提出了几个重要的问题。在体内长期抑制ADK是否能促进？细胞质量的扩大并预防糖尿病的发生？广泛表达的代谢酶如何选择性地控制特定细胞类型的生长？重要的是，成熟的人类？细胞对生长刺激具有抵抗力。目前，对于为什么人类？细胞似乎不具备复制能力，人们的理解非常有限。这项建议描述了一种系统的方法来回答这些关键问题，并揭示人类？细胞生长抵抗的分子基础。ADK基因和化学抑制的互补实验策略被用来评估ADK功能中断在体内的影响，并了解ADK是如何促进？细胞复制的。此外，ADK抑制剂促进啮齿动物？细胞复制的能力和创新的基于转录的策略被用来揭示为什么人类？细胞对生长刺激不敏感。这项工作的长期目标是发现刺激成熟的人类ç细胞再生的方法。

 DESCRIPTION (provided by applicant): Recent decades have seen an incredible growth in the prevalence of diabetes. The increasing frequency of this disorder threatens the health of our society and puts into focus the current lack of adequate prevention and treatment options. While it is important to pursue multiple therapeutic strategies, harnessing the regenerative capacity of islet ß-cells to increase an individual's insulin secretion capacity is among the promising approaches. Recently, discovery-oriented unbiased chemical screening led to the identification of the metabolic enzyme adenosine kinase (ADK) as a regulator of rodent and porcine ß-cell replication. Importantly, small molecule ADK-inhibitors selectively stimulate replication of ß-cels, but not alpha-cells, in vitro and in vivo. The identification of ADK as a regulator of ß-cell regeneration has raised several important questions. Does long-term inhibition of ADK in vivo promote ß-cell mass expansion and protect against developing diabetes? How does a broadly expressed metabolic enzyme selectively control the growth of a specific cell- type? Importantly, mature human ß-cells are resistant to growth stimuli. Presently, there is very limited understanding of why human ß-cells appear to be replication incompetent. This proposal describes a systematic approach to answering these critical questions and to uncovering the molecular basis of human ß- cell growth resistance. Complementary experimental strategies of genetic and chemical inhibition of ADK are employed to assess the in vivo impact of disrupting ADK function and to understand how ADKis promote ß-cell replication. Additionally, the ability of ADK inhibitors to promote rodent ß-cell replication and innovative transcriptomic-based strategies are leveraged to uncover why human ß-cells are refractory to growth stimuli. The long-term aim of this work is to uncover methods of stimulating mature human ß-cell regeneration.