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

基本信息

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
项目类别：
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

项目摘要

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，糖尿病的患病率不断增加，威胁着我们社会的健康，并使人们关注当前缺乏足够的预防和治疗方案的问题，尽管这一点很重要。为了追求多种治疗策略，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前景的方法之一。最近，以发现为导向的无偏见化学筛选导致了代谢酶腺苷激酶的鉴定。 (ADK) 作为啮齿动物和猪 β 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刺激 β 细胞复制，但不刺激 α 细胞。 β-细胞再生提出了几个重要的问题：体内 ADK 的长期抑制是否会促进 β-细胞增殖并预防糖尿病的发生？重要的是，成熟的人类 β 细胞对生长刺激具有抵抗力，目前，对于人类 β 细胞似乎无法复制的原因的了解非常有限。揭示人类β-细胞生长抗性的分子基础，采用 ADK 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。此外，利用 ADK 抑制剂促进啮齿动物 β 细胞复制的能力和基于转录组的创新策略来揭示人类 β 细胞对生长刺激不敏感的原因。揭示刺激成熟人类 ß 细胞再生的方法。