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.

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。