The Role of Adenosine Kinase in Controlling Beta-Cell Regeneration

腺苷激酶在控制 β 细胞再生中的作用

• 批准号: 8888112
• 负责人: Justin Pierce Annes
• 金额: $ 39.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888112
• 关键词: Acute; Address; Adenosine; Adenosine Kinase; Adverse effects; Age; Alpha Cell; American; Beta Cell; Blood Glucose; Cells; Chemicals; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Damage; Diabetes Mellitus; Disease; Dose; Economic Burden; Enzymes; Event; Excision; Family suidae; Frequencies; Gene Expression; Gene Expression Profile; Genetic; Glucose; Goals; Growth; Health; Hormones; Human; Hypoglycemia; In Vitro; Individual; Insulin; Islet Cell; Life; Measures; Mediating; Metabolic; Methods; Methylation; Methyltransferase; Mitogens; Molecular; Mus; Natural regeneration; Nucleotides; Pathway interactions; Pattern; Phosphorylation; Population; Prevalence; Prevention; Protein Isoforms; Protein Methylation; Proteins; Rattus; Reaction; Refractory; Repression; Resistance; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Societies; Sorting - Cell Movement; Stimulus; Streptozocin; Therapeutic; Treatment outcome; Work; base; cell dedifferentiation; cell growth; cell type; chemical genetics; comparative; differential expression; genome-wide; glucose tolerance; health economics; human FRAP1 protein; improved; in vivo; innovation; insulin secretion; islet; kinase inhibitor; leptin receptor; overexpression; pandemic disease; prevent; public health relevance; regenerative; response; screening; small molecule; transcriptome sequencing; transcriptomics; transmethylation

 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.

 描述（由申请人提供）：近几十年来，糖尿病的患病率出现了令人难以置信的增长。这种疾病的日益频繁威胁着我们社会的健康，并使目前缺乏适当的预防和治疗选择成为焦点。虽然追求多种治疗策略是重要的，但利用胰岛β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胰岛细胞复制的调节剂。重要的是，小分子ADK抑制剂在体外和体内选择性地刺激α-细胞而不是α-细胞的复制。ADK作为胰岛细胞再生调节因子的鉴定提出了几个重要的问题.体内长期抑制ADK是否促进胰岛细胞团的扩增并防止糖尿病的发生？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β细胞对生长刺激具有抗性。目前，对于为什么人类β细胞似乎不能复制的理解非常有限。该提案描述了一个系统的方法来回答这些关键问题，并揭示人类乳腺癌细胞生长阻力的分子基础。采用ADK的遗传和化学抑制的补充实验策略来评估破坏ADK功能的体内影响，并了解ADK如何促进β细胞复制。此外，ADK抑制剂促进啮齿动物β-细胞复制的能力和基于转录组学的创新策略被用来揭示为什么人类β-细胞对生长刺激物不敏感。这项工作的长期目标是揭示刺激成熟人类胰岛细胞再生的方法。