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The role ofglycosaminoglycan N-sulfation in glomerular biology/pathobiology

糖胺聚糖 N-硫酸化在肾小球生物学/病理学中的作用

基本信息

批准号：
10188513
负责人：
KEVIN John MCCARTHY
金额：
$ 42.87万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188513
关键词：
Adhesions Adult Affect Affinity Age Aging Animal Model Animals Architecture Basement membrane Binding Binding Sites Biology Carbohydrates Cell Adhesion Cell surface Cells Chronic Disease Chronic Kidney Failure Complication Core Protein Cytoskeletal Modeling Data Deacetylase Development Diabetes Mellitus Diabetic Nephropathy Elements End stage renal failure Enzymes Etiology Family Filtration Focal Adhesions Functional disorder Gene Deletion Heparan Sulfate Proteoglycan Heparitin Sulfate Homeostasis Hyperglycemia Hypertension In Vitro Incidence Individual Insulin-Dependent Diabetes Mellitus Integrin Binding Integrin alpha3beta1 Integrins Kidney Kidney Diseases Kidney Glomerulus Laboratories Length Ligand Binding Ligands Light Mediating Membrane Proteins Modification Molecular Nature Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Pattern Play Population Process Proteins Proteoglycan Regulation Renal function Role Signal Pathway Signal Transduction Specificity Sulfate System Testing Urologic Diseases copolymer diabetic economic impact glomerular basement membrane glomerular function glycation in vivo member migration mortality mutant mouse model organizational structure podocyte polysulfated glycosaminoglycan receptor sulfotransferase syndecan

项目摘要

The incidence of chronic kidney disease (CKD) in adults 60 and older increased from 18.8 to 24.5 percent between 1988-1994; currently this has risen to 26 percent. The mortality rate resulting from end stage renal disease (ESRD) is 150/1000 individuals in the population. In light of this information, it becomes important to identify key pathways that contribute to the development and the progression of CKD/ESRD. Over the past decade it has become recognized in the renal field that the glomerular podocyte is a key and critical determinant in the regulation of glomerular homeostasis. Recent studies have shown that the β1 integrins, primarily the α3β1 integrin heterodimer, mediate podocyte/glomerular basement membrane (GBM) interactions. It is also well known that integrin affinity for its respective ligand can be modified by the activity of intracellular signaling pathways (inside-out signaling or affinity modulation) and/or by the activity of cell surface co-receptors. Previous studies in other cell systems have shown that several members of the syndecan (Sdc) family of cell surface proteoglycans serve as cell adhesion co-receptors, which function alongside integrins in the formation of focal adhesions in most cells. Unlike integrins, the binding of Sdcs to their respective ligands is mediated primarily by the heparan sulfate glycosaminoglycan chains (HS) that are covalently attached to Sdc core proteins. Because the HS chains are capable of engaging/binding multiple ligands along the length of their chains, the interactions mediated by Sdc are promiscuous (many different ligand targets) and multiplexed (many ligand binding sites per HS chain). There is a degree of specificity in the HS-ligand interactions that is derived from the post-assembly modifications to HS, one key modification is the modification of the nascent carbohydrate chain during its assembly by the enzyme NDST1 (N- deacetylase-N-Sulfotransferase). The overarching Hypothesis for this current proposal is that decreased N- sulfation of heparan sulfate proteoglycans and/or modification of the HS binding sites on matrix protein ligands accelerates the development of diabetic nephropathy in individuals afflicted with either type I or type II diabetes mellitus. To test this hypothesis we propose the following Specific Aims: 1.) To conduct in vivo studies on potential changes in either the rate of development or the degree of progression of diabetic nephropathy in the kidneys of animal models in which NDST1 has been deleted in glomerular podocytes; 2.)To explore the effects of hyperglycemia on podocyte-matrix interactions in vitro in cells deficient for the enzyme NDST1.

60岁及以上成年人慢性肾脏疾病(CKD)的发病率从18.8上升到24.5 1988-1994年间为26%；目前这一比例已上升至26%。END导致的死亡率阶段性肾病(ESRD)在人口中的发病率为150/1000人。根据这些信息，它就变成了重要的是确定有助于慢性肾脏病/终末期肾病发展和进展的关键途径。在过去的十年里，肾脏领域已经认识到肾小球足细胞是一种关键和肾小球稳态调节中的关键决定因素。最近的研究表明，β1 整合素，主要是α3β1整合素异二聚体，介导足细胞/肾小球基底膜互动。众所周知，其相应配体的整合素亲和力可以通过以下活性来改变细胞内信号通路(内向外信号或亲和力调节)和/或细胞活动表面共受体。以前在其他细胞系统中的研究表明， Syndecan(SDC)家族的细胞表面蛋白多糖是细胞黏附的辅助受体，其功能与整合素一起在大多数细胞中形成局灶性粘连。与整合素不同的是，SDC与它们各自的配体主要由硫酸乙酰肝素糖胺聚糖链(HS)介导，这些糖胺聚糖链是共价连接到SDC核心蛋白上。因为HS链能够接合/结合多个配体沿着其链的长度，由SDC介导的相互作用是混杂的(许多不同配体靶标)和多重(每个HS链有多个配体结合位点)。有一定程度的特殊性从组装后对HS的修饰衍生的HS-配体相互作用，一个关键的修饰是新生的碳水化合物链在组装过程中被NDST1(N- 脱乙酰酶-N-磺基转移酶)。目前这一提议的首要假设是减少了N- 硫酸乙酰肝素蛋白多糖的硫酸化和/或骨架上HS结合位点的修饰蛋白配体加速糖尿病肾病患者的发展 I型或II型糖尿病。为了验证这一假设，我们提出了以下具体目标： 1)对发育速度或程度的潜在变化进行活体研究 NDST1缺失动物模型肾脏糖尿病肾病的研究进展 2.探讨高血糖对足细胞-基质相互作用的影响。缺乏NDST1酶的细胞。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of high glucose on glycosaminoglycans in cultured retinal endothelial cells and rat retina

DOI：
10.1093/glycob/cwac029
发表时间：
2022-05-12
期刊：
GLYCOBIOLOGY
影响因子：
4.3
作者：
Kaur, Gaganpreet;Song, Yuefan;Harris, Norman R.
通讯作者：
Harris, Norman R.

Functionalization of Electrospun Nanofibers and Fiber Alignment Enhance Neural Stem Cell Proliferation and Neuronal Differentiation.

DOI：
10.3389/fbioe.2020.580135
发表时间：
2020
期刊：
Frontiers in bioengineering and biotechnology
影响因子：
5.7
作者：
Amores de Sousa MC;Rodrigues CAV;Ferreira IAF;Diogo MM;Linhardt RJ;Cabral JMS;Ferreira FC
通讯作者：
Ferreira FC

Non-anticoagulant Heparin as a Pre-exposure Prophylaxis Prevents Lyme Disease Infection