权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Islet Endothelial Dysfunction in Diabetes

糖尿病中的胰岛内皮功能障碍

基本信息

批准号：
9237578
负责人：
REBECCA LUCY HULL-MEICHLE
金额：
$ 32.96万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
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：
2010-09-20 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237578
关键词：
ADAMTS Adult Affect Animal Model Area Atherosclerosis Basement membrane Beta Cell CD44 gene Cell Surface Receptors Cell Survival Cell physiology Cessation of life Cultured Cells Data Deposition Development Diabetes Mellitus Diabetic mouse Disease Disease Progression Elements Endothelial Cells Enzymes Extracellular Matrix Family member Functional disorder Funding Glucose Goals Human Hyaluronan Hyaluronidase Hyperglycemia Impairment In Vitro Insulin Integrin alpha6 Intervention Islets of Langerhans Knock-out Knockout Mice Knowledge Laminin Laminin Receptor Lesion Light Malignant Neoplasms Matrix Metalloproteinases Measures Modeling Non-Insulin-Dependent Diabetes Mellitus PTK2 gene Pathogenesis Patients Population Production Proteins Pulmonary Fibrosis Rattus Receptor Signaling Role Secretory Cell Signal Transduction Source TLR2 gene Testing Time Toll-like receptors United States Up-Regulation Viral Work db/db mouse diabetic endothelial dysfunction improved in vitro Model in vivo islet knock-down non-diabetic novel overexpression prevent public health relevance restoration transcription factor transcriptome sequencing

项目摘要

ABSTRACT Type 2 diabetes affects 9% of the United States population. Impairments in β-cell secretory function and survival are critical for the development of hyperglycemia. The mechanisms underlying β-cell dysfunction and death remain incompletely understood. Improving our knowledge of these is critical for the development of better therapies for this debilitating disease. The islet extracellular matrix (ECM), synthesized predominantly by islet endothelial cells, is a critical source of signals that impinge on the β-cell; ECM components laminin and hyaluronan normally enhance insulin release and/or β-cell survival. Our preliminary data in islets from human type 2 diabetes and animal models show for the first time that laminin production is decreased, hyaluronan is disrupted/fragmented, and expression of enzymes that can degrade or destabilize laminin and hyaluronan is increased. Our preliminary data also show these findings can be reproduced by culturing primary islet endothelial cells in high glucose. Further, we can reproduce β-cell dysfunction by culturing β-cells on this “diabetic” ECM or culturing them under conditions of laminin α4-deficiency or hyaluronan fragmentation. Thus, we hypothesize that in type 2 diabetes, reduced laminin production and/or signaling and increased hyaluronan fragmentation in islet endothelial-derived ECM impairs islet β-cell secretory function and survival. Our studies will encompass the following three specific aims: Specific Aim 1: To determine whether overexpression/inhibition of laminin α4 signaling improves/impairs insulin release. We will use viral overexpression to determine if restoration of normal laminin α4 levels in ECM from “diabetic” islet endothelial cells improves insulin release and/or β-cell survival in vitro. We will also knock out the laminin receptor subunit integrin α6 in β cells of adult, non-diabetic mice and assess insulin release in vivo. Specific Aim 2: To determine the mechanism(s) by which hyaluronan fragmentation in the islet ECM contributes to impaired insulin release and β-cell survival. Fragmented hyaluronan has been shown, in non- islet cells, to be proinflammatory, activating toll-like receptors (TLR) and NFκB. Here, we will determine if fragmented hyaluronan in islet ECM impairs β-cell function and survival via TLR2/4 and NFκB activation. Specific Aim 3. To determine whether upregulation of enzymes that destabilize hyaluronan (ADAMTSs) and degrade laminin (MMPs) precedes the onset of diabetes. Using RNA-Seq, we will determine if increases in islet endothelial expression of ADAMTS and MMP family members precede diabetes and/or increase with diabetes duration in UCD-T2DM rats and are increased in T2D human islets. We will validate observed changes at the protein and activity levels, and modulate expression of these enzymes in islet endothelial-derived ECM to evaluate their effects on insulin release and β-cell survival.

摘要