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Role of Rare Human Genetic Variants in LRP1 on Aortic Aneurysm Formation

LRP1 中罕见的人类遗传变异对主动脉瘤形成的作用

基本信息

批准号：
10421078
负责人：
Allison Lindsay Arai
金额：
$ 0.22万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421078
关键词：
10 year old Abdominal Aortic Aneurysm Affect Age Age-Months Alleles Aneurysm Aorta Aortic Aneurysm Aortic Rupture Atherosclerosis Attenuated Binding Biochemical Bioinformatics Blood Vessels Cell surface Cells Childhood Collaborations Data Defect Development Disease Elderly Embryo Endoplasmic Reticulum Exhibits Failure Genes Genetic Genetic study Goals Hemorrhage Heterozygote Homeostasis Human Human Genetics Impairment In Vitro Inherited LDL-Receptor Related Protein 1 Laboratories Lead Life Ligand Binding Ligands Link Low Density Lipoprotein Receptor Macroglobulins Mesoderm Microscopy Molecular Chaperones Mothers Mus Mutation Parents Pathway Analysis Pathway interactions Patients Pericytes Pharmacologic Substance Pharmacology Phenotype Physiological Platelet-Derived Growth Factor Receptor Population Property Proteins Proteomics Receptor Signaling Recycling Role Rupture Signal Pathway Signal Transduction Smooth Muscle Myocytes Structure Surface Plasmon Resonance Testing Thoracic Aortic Aneurysm Time Transforming Growth Factors Up-Regulation Vascular Smooth Muscle age group alpha 2-Glucoproteins base de novo mutation exome sequencing experimental study genetic variant improved insight loss of function male medical schools mutant new therapeutic target novel receptor receptor binding recruit trafficking uptake western diet

项目摘要

PROJECT SUMMARY Abdominal aortic aneurysms (AAA) affect a significant portion of the population and are typically associated with advanced age and atherosclerosis. Until now, no single gene has been identified as causative for AAA. Our laboratory has initiated studies to characterize biochemical defects in a patient with severe presentation of AAA in childhood. Two mutations on separate alleles were identified in the low density lipoprotein (LDL) receptor- related protein 1 (LRP1) gene of the patient. The LRP1 mutations include a de novo mutation in a ligand binding region and an inherited mutation in a β-propeller domain, a structure that is critical for LRP1 trafficking to the cell surface. We predict that the functional deficits caused by each mutation are related to the physiological role of the structural component where each mutation occurs. The LRP1 gene encodes a large endocytic and signaling receptor that binds and traffics numerous ligands to lysosomal compartment for degradation. Mouse studies reveal that selective deletion of LRP1 in vascular smooth muscle cells (smLRP1-/-) results in spontaneous and fully penetrant aortic aneurysm formation. A major goal of these proposed studies is biochemical characterization of the functional defects imposed by these mutant receptors, which will be critical to defining mechanisms by which LRP1 regulates vessel wall homeostasis. Interestingly, bioinformatic pathway analysis of quantitative proteomic results revealed excess signaling of the transforming growth factor- β (TGF-β) pathway in both patient aortic smooth muscle cells and the aorta of smLRP1-/- mice compared to controls. I hypothesize that loss of LRP1 function in the patient smooth muscle cells results from impaired ligand binding due to the de novo LRP1 mutation and from inefficient delivery of LRP1 to the cell surface due to the β-propeller domain LRP1 mutation. Furthermore, I hypothesize that the impact of these LRP1 mutations results in a loss of ability to attenuate the TGF-β signaling pathway. This hypothesis will be tested in the following specific aims: (1) to define the mechanism by which mutations in LRP1 result in excessive TGF-β signaling and (2) to determine the impact of patient LRP1 mutations on LRP1 trafficking. In vitro experiments will determine if patient-specific LRP1 mutations alter TGF-β protein levels and signaling. Surface plasmon resonance experiments will test if patient-specific LRP1 mutations result in defective binding of LRP1 to TGF-β, TGF-β binding partners, or molecular chaperones involved in LRP1 trafficking. Proteomic experiments will define the LRP1 interactome in control and patient-derived aortic smooth muscle cells to further identify defects in mutant LRP1 molecules. Finally, microscopy-based experiments will examine trafficking and recycling properties of mutant forms of LRP1. This study will demonstrate the link between AAA and two independent LRP1 mutations. The results will improve understanding of AAA formation to develop better treatments and identify novel pharmaceutical targets.

项目总结