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Identification of Genes and Compounds That Control Beta Cell Replication

控制β细胞复制的基因和化合物的鉴定

基本信息

批准号：
8044507
负责人：
DOUGLAS A MELTON
金额：
$ 439.57万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-25 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044507
关键词：
Address Affect Applied Genetics Area Beta Cell Biological Biological Assay Blood Glucose Cell Maintenance Cells Chemicals Chronic Development Diabetes Mellitus Disease Financial cost Gene Expression Profile Genes Genetic Transcription Goals Grant Health Human Hyperglycemia In Vitro Incidence Insulin Insulin Resistance Islets of Langerhans Lead Microarray Analysis Mus Neonatal Non-Insulin-Dependent Diabetes Mellitus Pancreatic Injury Patients Peripheral Population Pregnancy Proteins Rattus Regulator Genes Relative (related person)Research Role Screening procedure Signal Pathway Structure of beta Cell of islet Testing Therapeutic United States abstracting cell type diabetic drug candidate glycemic control improved in vitro Assay in vivo islet knock-down mouse model new therapeutic target novel prevent programs response small molecule stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): The research in this proposal will apply genetic, cell biological and chemical screening approaches with the goal of identifying novel treatments for type 2 diabetes (T2D), thus addressing thematic areas 1 and 2 of this grants program. Due to a relative deficiency in pancreatic beta cells, T2D patients are unable to produce sufficient insulin to control their blood glucose levels. If the number of beta cells in T2D patients could be increased, their glycemic control could be significantly improved, thus delaying or preventing the devastating consequences of chronic hyperglycemia. It is well established that beta cells possess the capacity to dramatically increase their numbers by replication, suggesting the possibility of harnessing this replicative potential as a therapeutic avenue for T2D. However, genes that specifically control beta cell replication are largely unknown. Likewise, small molecules that can boost beta cell replication rates have not been described. To identify genes that control beta cell replication, we propose to use microarray analysis to compare the transcription profiles of actively replicating populations of beta cells to the profiles of quiescent populations. In this way, we will be able to identify candidate regulatory genes whose expression either positively or negatively correlates with replication status. In parallel, we will undertake a high-throughput small molecule screen on cultured pancreatic islets to identify compounds that can stimulate the rate of beta cell replication in vitro. Genes and compounds identified by these two analyses will then be tested in mouse models to determine their ability to regulate beta cell replication in vivo. Thus, the studies in this proposal are likely to lead to the identification of novel therapeutic targets and drug candidates for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: The incidence of type 2 diabetes is rapidly increasing in the United States and worldwide. The negative impacts of long-term diabetes on a patient's health are significant, and carry with them a heavy financial burden. The therapies that will be developed as a result of the proposed research could be used to treat type 2 diabetes, and delay or prevent the devastating consequences of long-term disease. Thus, these therapies will both alleviate patient suffering while simultaneously reducing the financial costs of this disease.

描述（由申请人提供）：本提案中的研究将应用遗传学，细胞生物学和化学筛选方法，旨在确定2型糖尿病（T2D）的新型治疗方法，从而解决本赠款计划的主题领域1和2。由于胰腺β细胞的相对缺乏，T2D患者无法产生足够的胰岛素来控制他们的血糖水平。如果2型糖尿病患者的β细胞数量增加，他们的血糖控制可能会得到显着改善，从而延缓或预防慢性高血糖症的破坏性后果。众所周知，β细胞具有通过复制显著增加其数量的能力，这表明利用这种复制潜力作为T2D治疗途径的可能性。然而，特异性控制β细胞复制的基因在很大程度上是未知的。同样，可以提高β细胞复制率的小分子尚未被描述。为了确定控制β细胞复制的基因，我们建议使用微阵列分析来比较活跃复制的β细胞群体的转录谱与静止群体的转录谱。通过这种方式，我们将能够确定候选调控基因的表达与复制状态正相关或负相关。与此同时，我们将在培养的胰岛上进行高通量小分子筛选，以鉴定可以刺激体外β细胞复制速率的化合物。然后将在小鼠模型中测试通过这两种分析鉴定的基因和化合物，以确定它们在体内调节β细胞复制的能力。因此，该提案中的研究可能导致识别用于治疗糖尿病的新型治疗靶点和候选药物。公共卫生相关性：2型糖尿病的发病率在美国和世界范围内迅速增加。长期糖尿病对患者健康的负面影响是显著的，并带来沉重的经济负担。作为拟议研究的结果，将开发的疗法可用于治疗2型糖尿病，并延迟或预防长期疾病的破坏性后果。因此，这些疗法将减轻患者的痛苦，同时降低这种疾病的经济成本。