Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation
胰岛素降解酶:生理功能及其空间和活性调节
基本信息
- 批准号:10453700
- 负责人:
- 金额:$ 41.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAlzheimer&aposs DiseaseAmyloid beta-ProteinBindingBinding SitesBiological AssayCatabolismCell FractionationCell physiologyCellsCultured CellsDevelopmentDiabetes MellitusDiseaseEndosomesEnzyme ActivationEnzymesGenetic studyGoalsHuman GeneticsHydrolysisInositol PhosphatesInsulinInsulinaseKnowledgeLigandsLinkLipidsMembraneMicroscopyMonitorPeptide HydrolasesPeptidesPhosphatidylinositolsPhysiologicalPlayRegulationRoleSignal TransductionSiteSystemTechniquesTestingYeastsbaseendosome membraneenzyme activityenzyme substrateinhibitorinnovationinterestmutantnovelphosphatidylinositol 3-phosphatepolyanionreceptor internalizationreceptor mediated endocytosis
项目摘要
Insulin-degrading enzyme (IDE, insulysin) is a primarily cytosolic peptidase shown to be
important in the catabolism of insulin, the amyloid beta peptide, and likely other signaling and
intracellular peptides. Its cellular physiology is therefore of considerable interest in the treatment
of disorders such as diabetes and Alzheimer's disease. However the site of IDE action on these
peptides, which are internalized into or otherwise present in the endosomal system, is yet to be
fully understood. We propose to address the question of how this cytosolic enzyme encounters
substrate peptides, like insulin, in the endosomal system, exploring a novel mechanism for IDE
subcellular localization to this compartment. In particular, we propose that IDE is trafficked to
endosomes by binding to membrane anionic lipids, particularly phosphoinositides, through a
polyanion-binding site. In the first aim, we will test this hypothesis by using IDE polyanion site
mutants, by altering levels of a key phosphoinositide, and by expressing a phosphoinositide
binding competitor. We further propose to study, in the second aim, the participation of
endosomal IDE in insulin and amyloid(beta(peptide(catabolism. We will manipulate endosomal
IDE levels using mutant forms of the enzyme with reduced endosome localization, by
decreasing PtdIns(3)P levels, and by increasing endosomal IDE by fusing it with a PtdIns(3)P-
targeting domain. In the third aim, we will study the polyanion-dependent activation of IDE and
its role in affecting its catabolism of cytosolic peptides. We will use IDE mutants to test the effect
of activation on hydrolysis of peptide substrates identified using a ligand trapping technique and
peptidomic analyses. We will also test for activation of cellular IDE by inositol phosphates and
other potential endogenous activators. We will use our trapping technique to identify other
endogenous effectors. These studies will develop a clearer picture of how IDE carries out its
physiological functions and greatly benefit efforts to treat IDE related pathophysiological states.(
胰岛素降解酶(IDE,胰岛素)是一种主要的胞内肽酶。
在胰岛素的分解代谢中很重要,淀粉样β多肽,以及可能的其他信号和
胞内肽。因此,它的细胞生理学在治疗中引起了相当大的兴趣。
糖尿病和阿尔茨海默病等疾病的风险。然而,IDE对这些操作的站点
内化到或以其他方式存在于内体系统中的多肽,还有待于
完全理解。我们建议解决这个细胞质酶是如何遇到的问题
底物多肽,如胰岛素,在内体系统中,探索一种新的IDE机制
亚细胞定位到这个隔间。特别是,我们建议将IDE传输到
通过与膜上的阴离子脂类,特别是磷脂酰肌醇,通过一种
聚阴离子结合部位。在第一个目标中,我们将使用IDE多阴离子中心来验证这一假设
突变体,通过改变关键的肌醇磷脂的水平和表达肌醇磷脂
有约束力的竞争者。我们还建议,在第二个目标中,研究
胰岛素和淀粉样蛋白(β(多肽(分解代谢。我们将操控内吞体
利用酶的突变形式降低内体定位的IDE水平,通过
降低PtdIns(3)P水平,并通过将其与PtdIns(3)P-
目标域。在第三个目标中,我们将研究多阴离子依赖的IDE和
它在影响其胞浆多肽分解代谢中的作用。我们将使用IDE突变体来测试效果
用配基捕获技术鉴定的多肽底物的水解性活化和
多肽分析。我们还将测试肌醇磷酸和肌醇对细胞IDE的激活
其他潜在的内源性激活剂。我们将使用我们的诱捕技术来识别其他
内源性效应器。这些研究将更清楚地了解IDE是如何执行其
生理功能,对治疗IDE相关的病理生理状态大有裨益。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Louis B. Hersh其他文献
The Effect of Aliphatic Alcohols and Organic Solvents on Reactions Catalyzed by 5-Hydroxy-<em>N</em>-methylpyroglutamate Synthetase
- DOI:
10.1016/s0021-9258(19)45846-8 - 发表时间:
1971-12-25 - 期刊:
- 影响因子:
- 作者:
Louis B. Hersh - 通讯作者:
Louis B. Hersh
<em>N</em>-Methylglutamate Synthetase: THE USE OF FLAVIN MONONUCLEOTIDE IN OXIDATIVE CATALYSIS
- DOI:
10.1016/s0021-9258(19)43413-3 - 发表时间:
1973-10-10 - 期刊:
- 影响因子:
- 作者:
Robert J. Pollock;Louis B. Hersh - 通讯作者:
Louis B. Hersh
Effect of Vitamin B<sub>12</sub> Deprivation on the <em>in Vivo</em> Levels of Coenzyme A Intermediates Associated with Propionate Metabolism
- DOI:
10.1016/s0021-9258(19)42155-8 - 发表时间:
1974-11-10 - 期刊:
- 影响因子:
- 作者:
Eugene P. Frenkel;Richard L. Kitchens;Louis B. Hersh;Rene Frenkel - 通讯作者:
Rene Frenkel
Methylamine metabolism in a pseudomonas species.
假单胞菌属中的甲胺代谢。
- DOI:
- 发表时间:
1972 - 期刊:
- 影响因子:3.9
- 作者:
E. Bellion;E. Bellion;Louis B. Hersh;Louis B. Hersh - 通讯作者:
Louis B. Hersh
5-Hydroxy-<em>N</em>-methylpyroglutamate Synthetase: EVIDENCE FOR AN α-KETOGLUTARYL ENZYME INTERMEDIATE FROM PARTITIONING STUDIES
- DOI:
10.1016/s0021-9258(19)45917-6 - 发表时间:
1971-11-25 - 期刊:
- 影响因子:
- 作者:
Louis B. Hersh - 通讯作者:
Louis B. Hersh
Louis B. Hersh的其他文献
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{{ truncateString('Louis B. Hersh', 18)}}的其他基金
Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation
胰岛素降解酶:生理功能及其空间和活性调节
- 批准号:
10216310 - 财政年份:2019
- 资助金额:
$ 41.18万 - 项目类别:
Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation
胰岛素降解酶:生理功能及其空间和活性调节
- 批准号:
9817333 - 财政年份:2019
- 资助金额:
$ 41.18万 - 项目类别:
Neprilysin and Peripheral Clearance of Amyloid Peptides
脑啡肽酶和淀粉样肽的外周清除
- 批准号:
7858439 - 财政年份:2009
- 资助金额:
$ 41.18万 - 项目类别:
Center for Biomedical Research Excellence in the Molecular Basis of Human Disease
人类疾病分子基础卓越生物医学研究中心
- 批准号:
7919742 - 财政年份:2009
- 资助金额:
$ 41.18万 - 项目类别:
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