Developmental functions of adrenergic signaling in the pancreas

胰腺中肾上腺素信号的发育功能

基本信息

批准号：
9896821
负责人：
Eugene Eng Lin
金额：
$ 5.51万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896821
关键词：
Acute Address Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Adult Affect Age-Months Antibodies Architecture B-Cell Development Back Basement membrane Beta Cell Biological Assay Blood Glucose Blood Vessels Bypass CREB1 gene Calcium Cardiovascular Diseases Cell Count Cell membrane Cell physiology Chronic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Development Diabetes Mellitus Disease Distal Docking Electron Microscopy Endocrine Endothelial Cells Event Exhibits Exocytosis Fetal Development Functional disorder G-Protein-Coupled Receptors Glucagon Glucose Glucose Intolerance Glucose Transporter Goals Growth Hormones Hypertension Immunohistochemistry Impairment Insulin Islets of Langerhans Life Link Measures Mediating Mediator of activation protein Membrane Membrane Proteins Metabolic Metabolic Diseases Mitogens Molecular Morphology Mus Pancreas Pathway interactions Phosphorylation Physiological Potassium Channel Pregnant Women Production Public Health Research Risk Factors Role Signal Transduction Somatostatin Sympathetic Nervous System Testing Tissues Vascular Endothelial Growth Factors Vascularization beta-adrenergic receptor blood glucose regulation diabetes risk endocrine pancreas development experimental study fighting glucose metabolism glucose tolerance glucose uptake impaired glucose tolerance insight insulin granule insulin secretion insulin sensitivity islet mature animal mutant nerve supply pancreas development prevent recruit repaired response side effect uptake

项目摘要

PROJECT SUMMARY Diabetes is a disease that affects millions worldwide, and results from an inability to regulate blood glucose. β-cells residing in the islets of Langerhans in the pancreas control glucose levels through synthesis and secretion of insulin. However, this ability is lost in diabetes due to dysfunction or loss of β-cells. Better understanding of the mechanisms that control β-cell development and function will inform the treatment of diabetes. β-adrenergic receptors are key mediators of physiological responses to the sympathetic nervous system, and are abundantly expressed in the pancreas throughout life. However, the functions of adrenergic receptors in pancreas development have not been studied. This has significant public health implications as β- adrenergic receptor antagonists (β-blockers) are used to treat cardiovascular disease and hypertension in pregnant mothers, but the effects on fetal development remain unknown. Additionally, chronic inhibition of β- adrenoreceptors has adverse side-effects on glucose regulation and is a diabetes risk factor, but the underlying mechanisms have not been identified. Thus, there is a critical need to understand the essential roles of β-adrenergic receptors in both islet development and glucose homeostasis. Preliminarily, we have identified a tissue-specific role for the β-2 adrenergic receptor (Adrb2) in the development of the pancreatic islets of Langerhans, potentially by limiting vascular growth. We also find that pancreas-specific deletion of Adrb2 elicits functional defects in glucose tolerance and insulin secretion in mature mice. The overall goal of this proposal is to identify and characterize the mechanisms by which pancreas-specific Adrb2 expression controls islet development and glucose homeostasis. In Aim 1, we will assess the consequences of pancreas-specific Adrb2 deletion on islet morphology and vascularization, and define the signaling mechanisms by which Adrb2 regulates islet development. In Aim 2, we will address the effects of pancreas-specific Adrb2 loss on glucose homeostasis and insulin secretion in mature animals, and we will identify the molecular mechanisms by which Adrb2 signaling in β-cells influences insulin secretion. This study is the first to address developmental functions of β-adrenergic receptors in islets, classically studied in adult physiological responses, and to define a pancreas-specific role for β-adrenergic signaling in glucose homeostasis. Our findings have the potential to establish a new line of research in current translational efforts to treat metabolic disorders.

项目概要糖尿病是一种影响全世界数百万人的疾病，其原因是无法调节血液胰岛中的 β 细胞通过合成控制葡萄糖水平。然而，这种能力在糖尿病中会因 β 细胞功能障碍或丧失而丧失。了解控制 β 细胞发育和功能的机制将为治疗 β-肾上腺素能受体是交感神经生理反应的关键介质。系统，并且在整个生命过程中在胰腺中大量表达。然而，肾上腺素能的功能。尚未研究胰腺发育中的受体，这对于 β- 具有重大的公共健康影响。肾上腺素能受体拮抗剂（β-受体阻滞剂）用于治疗心血管疾病和高血压怀孕的母亲，但对胎儿发育的影响仍不清楚。此外，β-的慢性抑制。肾上腺素受体对血糖调节有不良副作用，是糖尿病的危险因素，但潜在机制尚未确定，因此迫切需要了解其本质。 β-肾上腺素能受体在胰岛发育和葡萄糖稳态中的作用。我们初步确定了 β-2 肾上腺素受体 (Adrb2) 在我们还发现，可能通过限制血管生长来抑制朗格汉斯胰岛的发育。胰腺特异性删除 Adrb2 会导致葡萄糖耐量和胰岛素分泌功能缺陷该提案的总体目标是确定和表征成熟小鼠的机制。胰腺特异性 Adrb2 表达控制胰岛发育和葡萄糖稳态在目标 1 中，我们将。评估胰腺特异性 Adrb2 缺失对胰岛形态和血管化的影响，以及定义 Adrb2 调节胰岛发育的信号机制。在目标 2 中，我们将解决以下问题。胰腺特异性 Adrb2 缺失对成熟动物葡萄糖稳态和胰岛素分泌的影响，以及我们将确定 β 细胞中 Adrb2 信号传导影响胰岛素分泌的分子机制。这项研究是第一个解决胰岛 β-肾上腺素能受体发育功能的研究，经典研究于成人生理反应，并定义葡萄糖中 β-肾上腺素能信号传导的胰腺特异性作用我们的研究结果有可能在当前的转化工作中建立一条新的研究路线。治疗代谢紊乱。