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: 10321556
• 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
• 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/10321556
• 关键词: Affinity; Aneurysm; Aorta; Aortic Aneurysm; 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; Lead; Ligands; Low Density Lipoprotein Receptor; Missense Mutation; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Pathway interactions; Patients; Peptide Hydrolases; Play; Problem Solving; Process; Proteins; Proteomics; Research Personnel; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Structure; Symptoms; System; Vascular Smooth Muscle; cell growth; inhibitor; insight; member; migration; mutant; novel therapeutic intervention; receptor; recruit; structural biology; transcriptome sequencing

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（LRP 1）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作用。通过培育一只LRP 1基因 在血管平滑肌细胞（SMC）中缺失，我们还发现LRP 1保护血管系统 动脉瘤的发展。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，LRP 1调节基质组装、TGF β 1信号传导和蛋白酶水平， 血管壁的活动。确定LRP 1调节这些事件的分子机制是一个 这是这次杰出研究者奖的目的。这些研究的重要性因以下因素而得到加强： LRP 1错义突变的淋巴瘤患者的鉴定。生化 这些突变受体所造成的功能缺陷的表征对于确定 LRP 1调节血管壁稳态的机制，代表了我们的另一个主要目标， 问题研究这将通过使用以下方法产生突变LRP 1取代的小鼠来实现： CRISPR/Cas9系统。LRP 1以高亲和力与超过40种配体相互作用，尽管付出了大量努力， 关于受体/配体复合物的性质的信息非常少。我们亦建议 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， LRP 1的结构是LRP 1B，LRP 1B是另一种在SMC中丰富并调节其迁移的受体， 以未知的机制扩散。我们建议进行遗传、蛋白质组和RNA-seq分析， 这种受体调节SMC生长的机制。这些研究将共同确定 LDL受体家族成员通过其保护血管系统免受疾病的影响， LRP 1错义突变患者的治疗方法。