Use of Zebrafish as a Model for Diabetic Nephropathy
使用斑马鱼作为糖尿病肾病模型
基本信息
- 批准号:6622910
- 负责人:
- 金额:$ 15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-04-01 至 2005-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): A thickening in basement membranes (BM) is
a common secondary complication of diabetes and is associated with
abnormalities in kidney function when the glomerular BM (GBM) is affected.
While the mechanisms underlying GBM thickening are not understood, it is
evident that the normal biosynthesis and maintenance of GBM is an important
aspect of kidney function. GBM thickening can be explained in terms of problems
in the balance of matrix component synthesis, polymerization, and turnover.
These processes all involve cell/ECM interactions to some degree and imply that
GBM formation is tightly controlled. To understand the mechanisms underlying
GBM formation and maintenance under normal and pathological conditions, we
propose to utilize the zebrafish (ZF) as a model system. The ZF lends itself to
such studies because its renal system develops rapidly and the organism is
amendable to cellular, molecular, and genetic approaches. The ZF renal system
develops in two stages including:
1) formation of a transient pronephros by 50 hrs of development that is
composed of a single glomerulus and 2) formation of a mesonephros by the 3d
week that contains multiple glomeruli as seen in mammals. Unlike the
pronephros, the ZF mesonephric kidney has not been well studied although it is
required for studies related to GBM formation, maturation, and turnover. The
specific aims of this two-year R21 (Exploratory/Developmental Grant) will focus
on establishing the ZF as a model for analysis of GBM formation and turnover in
the mesonephric kidney under normal conditions and conditions of elevated
glucose levels as observed in diabetes. The Specific Aims will include: 1) to
determine if isoform switching of BM components occurs during maturation of the
ZF mesonephric glomerulus, 2) development of procedures to target expression of
GBM components and associated matrix metalloproteinases (MMP5) in the
mesonephric kidney of transgenic ZF, 3) to determine if elevated glucose levels
result in glycation of proteins in the GBM and if a thickening of the GBM
occurs as observed in rodent kidney models, and 4) initiation of experiments
using the above mentioned GBM compositional data and transgenic procedures to
begin to test the hypothesis that 'GBM thickening in the ZF mesonphric kidney
involves a disruption in the normal balance between the polymerization and
turnover of matrix components due to non-enzymatic glycation of matrix
components that makes them less susceptible to cleavage by MMPs."
描述(由申请人提供):基底膜(BM)增厚,
糖尿病常见的继发性并发症,
当肾小球BM(GBM)受到影响时,肾功能异常。
虽然GBM增厚的机制尚不清楚,但它是
很明显,GBM的正常生物合成和维持是一个重要的
肾功能方面。GBM增厚可以解释为
在基质组分合成、聚合和周转的平衡中。
这些过程都在一定程度上涉及细胞/ECM相互作用,并意味着
GBM的形成受到严格控制。为了了解这些现象背后的机制,
在正常和病理条件下GBM的形成和维持,我们
建议利用斑马鱼(ZF)作为模型系统。ZF有助于
这种研究,因为它的肾脏系统发展迅速,
适用于细胞、分子和遗传学方法。ZF肾脏系统
发展分为两个阶段,包括:
1)通过50小时的发育形成短暂的前肾,
由单个肾小球组成,2)由3d形成中肾
哺乳动物中含有多个肾小球的一周。不像
尽管ZF中肾肾在前肾,但尚未得到很好的研究,
这是与GBM形成、成熟和周转相关的研究所必需的。的
这项为期两年的R21(探索/发展赠款)的具体目标将集中在
建立ZF作为分析GBM形成和周转的模型,
中肾在正常条件下和升高条件下
糖尿病患者的血糖水平。具体目标包括:1)
确定BM组分的同种型转换是否发生在
ZF中肾肾小球,2)开发靶向表达
GBM组分和相关的基质金属蛋白酶(MMP 5)在
转基因ZF的中肾,3)以确定是否升高的葡萄糖水平
导致GBM中蛋白质的糖化,并且如果GBM的增厚
如在啮齿动物肾脏模型中观察到的那样发生,以及4)实验开始
使用上述GBM组成数据和转基因程序,
开始检验ZF中肾GBM增厚的假设
涉及聚合和聚合之间的正常平衡的破坏,
由于基质的非酶糖化导致基质组分的转换
这使得它们不易被MMPs切割。"
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Limb regeneration is impaired in an adult zebrafish model of diabetes mellitus.
- DOI:10.1111/j.1524-475x.2010.00613.x
- 发表时间:2010-09
- 期刊:
- 影响因子:0
- 作者:Olsen AS;Sarras MP Jr;Intine RV
- 通讯作者:Intine RV
Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression.
- DOI:10.2337/db11-0588
- 发表时间:2012-02
- 期刊:
- 影响因子:7.7
- 作者:Olsen AS;Sarras MP Jr;Leontovich A;Intine RV
- 通讯作者:Intine RV
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MICHAEL Peter SARRAS其他文献
MICHAEL Peter SARRAS的其他文献
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{{ truncateString('MICHAEL Peter SARRAS', 18)}}的其他基金
Developing and Improving Institutional Animal Resources at Rosalind Franklin Un.
罗莎琳德·富兰克林大学开发和改善机构动物资源。
- 批准号:
7628240 - 财政年份:2009
- 资助金额:
$ 15万 - 项目类别:
Use of Zebrafish as a Model for Diabetic Nephropathy
使用斑马鱼作为糖尿病肾病模型
- 批准号:
6459153 - 财政年份:2002
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR GLUCOSE INDUCED BASEMENT MEMBRANE THICKENING
葡萄糖引起的基底膜增厚模型
- 批准号:
2147717 - 财政年份:1995
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR GLUCOSE INDUCED BASEMENT MEMBRANE THICKENING
葡萄糖引起的基底膜增厚模型
- 批准号:
2734150 - 财政年份:1995
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR GLUCOSE INDUCED BASEMENT MEMBRANE THICKENING
葡萄糖引起的基底膜增厚模型
- 批准号:
2147718 - 财政年份:1995
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR GLUCOSE INDUCED BASEMENT MEMBRANE THICKENING
葡萄糖引起的基底膜增厚模型
- 批准号:
2444097 - 财政年份:1995
- 资助金额:
$ 15万 - 项目类别:
A MODEL FOR BASEMENT MEMBRANE THICKENING IN DIABETES
糖尿病基底膜增厚的模型
- 批准号:
3426184 - 财政年份:1991
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR EPITHELIAL/BASEMENT MEMBRANE INTERACTIONS
上皮/基底膜相互作用模型
- 批准号:
2283225 - 财政年份:1990
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR EPITHELIAL/BASEMENT MEMBRANE INTERACTIONS
上皮/基底膜相互作用模型
- 批准号:
3421551 - 财政年份:1990
- 资助金额:
$ 15万 - 项目类别:
MODEL FOR EPITHELIAL/BASEMENT MEMBRANE INTERACTIONS
上皮/基底膜相互作用模型
- 批准号:
3421548 - 财政年份:1990
- 资助金额:
$ 15万 - 项目类别:
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