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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.