Role of LDL receptor family members in protecting the vasculature
LDL受体家族成员在保护脉管系统中的作用
基本信息
- 批准号:10321556
- 负责人:
- 金额:$ 77.25万
- 依托单位:
- 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:2017-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAneurysmAortaAortic AneurysmAwardBiochemicalBlood VesselsCRISPR/Cas technologyCellsCessation of lifeClinical DataCollagenComplexCountryDataDefectDepositionDevelopmentDilatation - actionDiseaseDissectionElastinEventFamily memberGenerationsGenesGeneticGoalsHomeostasisInflammatoryInterventionLDL-Receptor Related Protein 1LeadLigandsLow Density Lipoprotein ReceptorMissense MutationModelingMolecularMusNatureOperative Surgical ProceduresPathway interactionsPatientsPeptide HydrolasesPlayProblem SolvingProcessProteinsProteomicsResearch PersonnelRoleRuptureSignal TransductionSmooth Muscle MyocytesStructureSymptomsSystemVascular Smooth Musclecell growthinhibitorinsightmembermigrationmutantnovel therapeutic interventionreceptorrecruitstructural biologytranscriptome sequencing
项目摘要
The LDL-receptor related protein 1 (LRP1) is a highly efficient endocytic and a signal transducing receptor that
plays an important role in vascular development. By developing a mouse in which LRP1 was genetically
deleted in vascular smooth muscle cells (SMC), we have also discovered that LRP1 protects the vasculature
from the development of aneurysms. Currently, mechanisms by which this occurs are not well understood, but
our studies thus far reveal that LRP1 regulates matrix assembly, TGF signaling, and levels of protease
activity in the vessel wall. Defining the molecular mechanism by which LRP1 regulates these events is one
goal of this Outstanding Investigator Award. The significance of these studies are enhanced by the
identification of patients with aneurysmal disease harboring missense mutations in LRP1. Biochemical
characterization of the functional defects imposed by these mutant receptors will be critical to define the
mechanisms by which LRP1 regulates vessel wall homeostasis, and represents another major goal of our
studies. This will be accomplished by a the generation of mutant LRP1 substituted mice employing the
CRISPR/Cas9 system. LRP1 interacts with over 40 ligands with high affinity, and despite substantial effort,
very little information is available regarding the nature of the receptor/ligand complex. We also propose
strategies to solve this problem using the latest technological advances in structural biology. Closely related in
structure to LRP1 is LRP1B, another receptor that is abundant in SMC and regulates their migration and
proliferation by unknown mechanisms. We propose genetic, proteomic and RNA-seq analysis to identify
mechanisms by which this receptor regulates SMC growth. Together, the studies will define the mechanisms
by which LDL receptor family members protect the vasculature from disease and may identify novel
therapeutic approaches for patients harboring LRP1 missense mutations.
LDL受体相关蛋白1(LRP1)是一种高效的内吞和信号转导的受体,该受体是该受体
在血管发育中起着重要作用。通过开发LRP1的鼠标。
在血管平滑肌细胞(SMC)中删除,我们还发现LRP1保护脉管系统
来自动脉瘤的发展。目前,发生这种情况的机制尚不清楚,但是
迄今为止,我们的研究表明,LRP1调节基质组件,TGF信号传导和蛋白酶水平
在容器壁上的活动。定义LRP1调节这些事件的分子机制是一种
这个杰出调查员奖的目标。这些研究的意义得到了增强
鉴定患有LRP1错义突变的动脉瘤疾病患者。生化
这些突变受体施加的功能缺陷的表征对于定义
LRP1调节船只壁稳态的机制,代表了我们的另一个主要目标
研究。这将是通过使用使用该突变体LRP1取代的小鼠来实现的
CRISPR/CAS9系统。 LRP1与40多个具有高亲和力的配体相互作用,并且需要大量的努力,
关于接收器/配体综合体性质的信息很少。我们也建议
使用结构生物学的最新技术进步来解决此问题的策略。密切相关
LRP1的结构是LRP1B,这是SMC中丰富的另一个接收器,并调节其迁移和
未知机制的增殖。我们提出了遗传,蛋白质组学和RNA-seq分析
该接收器调节SMC增长的机制。研究将共同定义机制
LDL受体家族成员通过其中保护脉管系统免受疾病的侵害,并可能识别出新的
具有LRP1错义突变的患者的治疗方法。
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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Dudley K. Strickland其他文献
Role for Low-Density Lipoprotein Receptor-Related Protein 1 in Vessel Wall Homeostasis
- DOI:
10.1016/j.jamcollsurg.2018.07.613 - 发表时间:
2018-10-01 - 期刊:
- 影响因子:
- 作者:
Brittany O. Aicher;Rebeca Galisteo;Selen C. Muratoglu;Areck A. Ucuzian;Dudley K. Strickland - 通讯作者:
Dudley K. Strickland
130 Characterization of a novel endothelial receptor, LR3, that defines a new class of receptors related to the LDL receptor family
- DOI:
10.1016/s0268-9499(97)80246-9 - 发表时间:
1997-10-01 - 期刊:
- 影响因子:
- 作者:
Todd A. Hembrough;Frances D. Battey;Jeffrey A. Winkles;Dudley K. Strickland - 通讯作者:
Dudley K. Strickland
Dudley K. Strickland的其他文献
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{{ truncateString('Dudley K. Strickland', 18)}}的其他基金
Upgrading the CVID Biosensor Core Facility with a Biacore 8K instrument
使用 Biacore 8K 仪器升级 CVID 生物传感器核心设施
- 批准号:
10176937 - 财政年份:2021
- 资助金额:
$ 77.25万 - 项目类别:
Role of LDL receptor family members in protecting the vasculature
LDL受体家族成员在保护脉管系统中的作用
- 批准号:
10078621 - 财政年份:2017
- 资助金额:
$ 77.25万 - 项目类别:
Role of LDL receptor family members in protecting the vasculature
LDL受体家族成员在保护脉管系统中的作用
- 批准号:
10532199 - 财政年份:2017
- 资助金额:
$ 77.25万 - 项目类别:
Mechanisms by which LRP1 Protects the Vasculature
LRP1 保护脉管系统的机制
- 批准号:
9002897 - 财政年份:2014
- 资助金额:
$ 77.25万 - 项目类别:
Mechanisms by which LRP1 Protects the Vasculature
LRP1 保护脉管系统的机制
- 批准号:
8722143 - 财政年份:2014
- 资助金额:
$ 77.25万 - 项目类别:
Role of Lipoprotein Receptors in Venous Thrombosis
脂蛋白受体在静脉血栓形成中的作用
- 批准号:
8435382 - 财政年份:2012
- 资助金额:
$ 77.25万 - 项目类别:
Role of Lipoprotein Receptors in Venous Thrombosis
脂蛋白受体在静脉血栓形成中的作用
- 批准号:
8320618 - 财政年份:2012
- 资助金额:
$ 77.25万 - 项目类别:
Role of Lipoprotein Receptors in Venous Thrombosis
脂蛋白受体在静脉血栓形成中的作用
- 批准号:
8814273 - 财政年份:2012
- 资助金额:
$ 77.25万 - 项目类别:
Role of Lipoprotein Receptors in Venous Thrombosis
脂蛋白受体在静脉血栓形成中的作用
- 批准号:
8623147 - 财政年份:2012
- 资助金额:
$ 77.25万 - 项目类别:
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相似海外基金
Role of LDL receptor family members in protecting the vasculature
LDL受体家族成员在保护脉管系统中的作用
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10078621 - 财政年份:2017
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