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.
低密度脂蛋白受体相关蛋白1(LRP1)是一种高效的内吞和信号转导受体。
在血管发育中起着重要的作用。通过开发一种具有LRP1基因的小鼠
我们还发现,在血管平滑肌细胞(SMC)中缺失的LRP1对血管系统具有保护作用
与动脉瘤的发展有关。目前,这种现象发生的机制还不是很清楚,但
到目前为止,我们的研究表明,lrp1调节基质组装、转化生长因子信号转导和蛋白水解酶水平。
血管壁上有活动。确定LRP1调节这些事件的分子机制是一种
这一杰出调查者奖的目标。这些研究的意义因以下原因而得到加强
识别存在LRP1错义突变的动脉瘤性疾病患者。生化
对这些突变受体造成的功能缺陷的表征将是确定
LRP1调节血管壁内稳态的机制,并代表了我们的另一个主要目标
学习。这将通过一代突变的LRP1替换小鼠来实现,该小鼠使用
CRISPR/CAS9系统。LRP1与40多个高亲和力的配体相互作用,尽管付出了大量的努力,
关于受体/配体复合体的性质的信息很少。我们还提议
利用结构生物学的最新技术进步来解决这个问题的策略。密切相关的
LRP1的结构是LRP1B,它是SMC中含量丰富的另一种受体,调节它们的迁移和
以未知的机制进行扩散。我们建议用遗传学、蛋白质组学和rna-seq分析来鉴定
该受体调节SMC生长的机制。总之,这些研究将定义这些机制
低密度脂蛋白受体家族成员通过什么来保护血管系统免受疾病的影响,并可能识别新的
携带LRP1错义突变患者的治疗方法。
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
NMR assignment of domain 3 of the receptor-associated protein (RAP)
- DOI:
10.1007/s10858-006-9036-7 - 发表时间:
2006-10-03 - 期刊:
- 影响因子:1.900
- 作者:
Donghan Lee;Joseph D. Walsh;Ping Yu;Molly Migliorini;Yibing Wu;Dudley K. Strickland;Yun-Xing Wang - 通讯作者:
Yun-Xing Wang
NMR assignment of domain 2 of the receptor-associated protein
- DOI:
10.1007/s10858-006-9034-9 - 发表时间:
2006-07-25 - 期刊:
- 影响因子:1.900
- 作者:
Joseph D. Walsh;Donghan Lee;Ping Yu;Molly Migliorini;Dudley K. Strickland;Yun-Xing Wang - 通讯作者:
Yun-Xing Wang
The low-density lipoprotein receptor-related protein-1 (LRP1) in Schwann cells controls mitochondria homeostasis in peripheral nerves
雪旺细胞中的低密度脂蛋白受体相关蛋白-1(LRP1)控制周围神经中的线粒体稳态
- DOI:
10.1016/j.pneurobio.2025.102796 - 发表时间:
2025-08-01 - 期刊:
- 影响因子:6.100
- 作者:
Stefano Martellucci;Melissa Heredia;Zixuan Wang;Thomas Whisenant;Dudley K. Strickland;Richard Sanchez;Takahito Arai;Morgan Zhang;Haoming Wang;Zhiting Gong;Kesava Asam;Brad E. Aouizerat;Gulcin Pekkurnaz;Yi Ye;Wendy M. Campana - 通讯作者:
Wendy M. Campana
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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