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：
10532199
负责人：
Dudley K. Strickland
金额：
$ 77.25万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
https://reporter.nih.gov/project-details/10532199
关键词：
Affinity Aneurysm Aortic Aneurysm Aortic Rupture Award Biochemical Blood Vessels CRISPR/Cas technology Cells Cessation of life Clinical Data Collagen Complex Country Data Defect Deposition Development Dilatation - action Disease Dissection Elastin Event Family member Generations Genes Genetic Goals Homeostasis Inflammatory Intervention LDL-Receptor Related Protein 1 Ligands Low Density Lipoprotein Receptor Missense Mutation Modeling Molecular Mus Nature Operative Surgical Procedures Pathway interactions Patients Peptide Hydrolases Play Process Proliferating Proteins Proteomics Research Personnel Role Rupture Signal Transduction Smooth Muscle Myocytes Structure Symptoms System Technology Vascular Smooth Muscle cell growth inhibitor insight member migration mutant novel therapeutic intervention receptor recruit structural biology transcriptome 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受体，通过培育出具有 LRP1 基因的小鼠，在血管发育中发挥重要作用。在血管平滑肌细胞（SMC）中删除LRP1后，我们还发现LRP1可以保护血管系统目前，这种情况发生的机制尚不清楚，但迄今为止，我们的研究表明 LRP1 调节基质组装、TGF 信号传导和蛋白酶水平定义 LRP1 调节这些事件的分子机制是其中之一。杰出研究者奖的目标增强了这些研究的重要性。鉴定患有 LRP1 错义突变的动脉瘤疾病患者。这些突变受体造成的功能缺陷的表征对于定义 LRP1 调节血管壁稳态的机制，代表了我们的另一个主要目标这将通过使用 LRP1 突变小鼠的产生来完成。 CRISPR/Cas9 系统以高亲和力与 40 多种配体相互作用，尽管付出了巨大的努力，我们还提出关于受体/配体复合物性质的信息非常少。利用结构生物学的最新技术进步来解决这个问题的策略。 LRP1 的结构是 LRP1B，它是 SMC 中丰富的另一种受体，调节其迁移和我们建议通过遗传、蛋白质组和 RNA-seq 分析来识别。这些研究将共同确定该受体调节 SMC 生长的机制。 LDL 受体家族成员可通过其保护脉管系统免受疾病侵害，并可识别新的针对携带 LRP1 错义突变的患者的治疗方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Murine Aortic Crush Injury: An Efficient In Vivo Model of Smooth Muscle Cell Proliferation and Endothelial Function.

小鼠主动脉挤压伤：平滑肌细胞增殖和内皮功能的有效体内模型。

DOI：
10.3791/55201
发表时间：
2017
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Yu,Dan;Makkar,George;Sarkar,Rajabrata;Strickland,DudleyK;Monahan,ThomasS
通讯作者：
Monahan,ThomasS

Current View on the Molecular Mechanisms Underlying Fibrin(ogen)-Dependent Inflammation.

DOI：
10.1055/a-1910-4538
发表时间：
2022-11
期刊：
Thrombosis and haemostasis
影响因子：
6.7
作者：
通讯作者：

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts.

DOI：
10.1111/jth.15817
发表时间：
2022-10
期刊：
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
影响因子：
10.4
作者：
Chun, Haarin;Kurasawa, James H.;Olivares, Philip;Marakasova, Ekaterina S.;Shestopal, Svetlana A.;Hassink, Gabriela U.;Karnaukhova, Elena;Migliorini, Mary;Obi, Juliet O.;Smith, Ally K.;Wintrode, Patrick L.;Durai, Prasannavenkatesh;Park, Keunwan;Deredge, Daniel;Strickland, Dudley K.;Sarafanov, Andrey G.
通讯作者：
Sarafanov, Andrey G.

Role of the LDL Receptor-Related Protein 1 in Regulating Protease Activity and Signaling Pathways in the Vasculature.

DOI：
10.2174/1389450119666180511162048
发表时间：
2018
期刊：
Current drug targets
影响因子：
3.2
作者：
Au DT;Arai AL;Fondrie WE;Muratoglu SC;Strickland DK
通讯作者：
Strickland DK

Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors.

DOI：
10.1016/j.jbc.2021.100842
发表时间：
2021-07
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Marakasova E;Olivares P;Karnaukhova E;Chun H;Hernandez NE;Kurasawa JH;Hassink GU;Shestopal SA;Strickland DK;Sarafanov AG
通讯作者：
Sarafanov AG