Mechanisms by which LRP1 Protects the Vasculature

LRP1 保护脉管系统的机制

• 批准号: 8722143
• 负责人: Dudley K. Strickland
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722143
• 关键词: Abdominal Aortic Aneurysm; Accounting; Acute; Affect; Amino Acid Substitution; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Atherosclerosis; Binding; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Cells; Cessation of life; Chest; Chymase; Clinical Data; Collaborations; Collagen; Coronary; Country; DNA; Data; Deposition; Development; Dideoxy Chain Termination DNA Sequencing; Dilatation - action; Disease; Dissection; Elastic Fiber; Elastin; Elderly; Event; Extracellular Matrix; Family; Family member; Filament; Gene Mutation; Genes; Genetic; Genetic Determinism; Heart; High temperature of physical object; Human; Inflammatory; Inherited; Intervention; LDL-Receptor Related Protein 1; Lead; Ligand Binding; Mediating; Modeling; Molecular; Mus; Muscle Contraction; Mutation; Operative Surgical Procedures; Orthologous Gene; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Physiological Processes; Physiology; Plant Roots; Plasma; Predisposition; Process; Proteins; Proteomics; Receptor Signaling; Role; Rupture; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Symptoms; Testing; Thoracic Aortic Aneurysm; Variant; Vascular Proliferation; Vascular Smooth Muscle; age group; exome sequencing; genome wide association study; human disease; in vivo; inhibitor/antagonist; macrophage; mast cell protease 4; prevent; public health relevance; rare variant; receptor; receptor function; research study

Aortic aneurysms and aortic dissections account for 1% to 2% of all deaths in Western countries, and are usually asymptomatic until they rupture which most often results in death. Unfortunately, our current understanding of the molecular mechanisms leading to aneurysm formation is limited. Genome wide association studies reveal that the Lrp1 gene represents a susceptibility locus for abdominal aortic aneurysms. LRP1 encodes the LDL receptor related protein 1 (LRP1), a large endocytic and signaling receptor that regulates important physiological processes. Our recent studies reveal that mice in which the Lrp1 gene is selectively deleted in smooth muscle cells (smLRP1-/- mice) develop thoracic aneurysms. These mice display all of the symptoms detected in the human disease, including extensive in vivo aortic root and thoracic aortic dilatation, elastic lamina disorganization, recruitment of inflammatory cells into the vessel wall and excess collagen deposition. Proteomic studies revealed accumulation of proteases in the vessel wall, including HtrA1 (high-temperature requirement factor A1) and mast cell protease 4 (mMCP-4), the murine ortholog of human chymase. Both of these proteases are involved in matrix and elastic lamina degradation. Studies in Aim 1 will test the hypothesis that SMC LRP1 protects the vasculature by modulating protease activity, especially HtrA1 and mMCP-4, which in turn regulates the integrity of the elastic laminae. Ultrastructure studies of the aortic wall in smLRP1-/- mice reveal abnormal SMC. The TGF signaling pathway is a major pathway that is responsible for maintaining SMC in a contractile phenotype, and our preliminary data reveal that LRP1 binds several TGF family members and is required for the non-canonical signaling mediated by TGF Experiments in Aim 2 will test the hypothesis that LRP1 modulates SMC phenotypic transitions by regulating the TGF signaling pathway. Finally, we have initiated studies in collaboration with Dianna Milewicz (UT Houston) who has performed exome and Sanger sequencing of DNA from families with thoracic aortic aneurysms and acute aortic dissections. These studies identified several extremely rare LRP1 variants that segregate with aortic disease in these families, providing strong evidence that they are associated with the disease. Analysis of the amino acid substitutions in several of these variants suggest a strong rational for altered ligand binding and altered function in LRP1. Studies in Aim 3 will test the hypothesis that these rare variants result in defective LRP1 function, which in turn contributes to the development of this disease.

主动脉瘤和主动脉夹层占西方国家所有死亡人数的 1% 至 2% 国家，并且通常无症状，直到破裂，这通常导致死亡。 不幸的是，我们目前对导致动脉瘤的分子机制的理解 形成是有限的。全基因组关联研究表明 Lrp1 基因代表 腹主动脉瘤的易感位点。 LRP1编码LDL受体相关 蛋白 1 (LRP1)，一种大型内吞和信号传导受体，可调节重要的生理功能 流程。我们最近的研究表明，Lrp1 基因被选择性删除的小鼠 平滑肌细胞（smLRP1-/- 小鼠）会形成胸动脉瘤。这些小鼠显示了所有 在人类疾病中检测到的症状，包括广泛的体内主动脉根部和 胸主动脉扩张、弹力层瓦解、炎症细胞募集 血管壁和多余的胶原蛋白沉积。蛋白质组学研究揭示了 血管壁中的蛋白酶，包括 HtrA1（高温要求因子 A1）和肥大 细胞蛋白酶 4 (mMCP-4)，人类食糜酶的鼠类直系同源物。这两种蛋白酶都是 参与基质和弹性层降解。目标 1 的研究将检验以下假设： SMC LRP1 通过调节蛋白酶活性（尤其是 HtrA1 和 HtrA1）来保护脉管系统 mMCP-4，反过来调节弹性层的完整性。超微结构研究 smLRP1-/- 小鼠的主动脉壁显示出异常的 SMC。 TGF 信号通路是 负责维持 SMC 收缩表型的主要途径，以及我们的 初步数据显示，LRP1 结合多个 TGF 家族成员，并且是 由 TGF 介导的非规范信号传导 目标 2 中的实验将检验以下假设： LRP1 通过调节 TGF 信号通路来调节 SMC 表型转变。 最后，我们与 Dianna Milewicz（UT 休斯顿）合作开展了研究，她 对胸主动脉瘤家族的 DNA 进行外显子组和桑格测序 和急性主动脉夹层。这些研究发现了几种极其罕见的 LRP1 变体 这些家庭中患有主动脉疾病，这提供了强有力的证据表明他们是 与疾病有关。分析其中几个的氨基酸取代 变异表明 LRP1 中配体结合的改变和功能的改变具有强有力的合理性。 目标 3 中的研究将检验这些罕见变异导致 LRP1 缺陷的假设 功能，进而促进这种疾病的发展。