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    The Role of LRP1 in Inflammation and Vasculopathies

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    Author
    Au, Dianaly
    0000-0002-8797-833X
    Advisor
    Strickland, Dudley K.
    Catania, Selen M.
    Date
    2018
    Embargo until
    07/01/2019
    Type
    dissertation
    
    Metadata
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    Abstract
    The prevalence of overweight and obesity and a growing aging population has resulted in higher incidences of type 2 diabetes (T2D) and cardiovascular disease (CVD). Although risk factors for T2D and CVD have been known for decades, the molecular mechanisms involved in the pathophysiology of these multifaceted diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundantly expressed in several tissues and possesses diverse biological functions, including chylomicron remnant clearance, involvement in insulin signaling and glucose homeostasis, modulation of the inflammatory response, atheroprotection, and maintenance of vascular integrity. We hypothesized that LRP1 may serve as a molecular link between metabolic processes and CVD development and employed tissue-specific LRP1 knockout mouse models to identify potential molecular mechanisms. Studies performed on macrophage-specific LRP1-deficient mice generated on an LDL receptor knockout background (LDLR-/-; macLRP1-/-) and challenged with a Western diet revealed that LRP1 expression in macrophages promotes hepatic inflammation and the development of glucose intolerance and insulin resistance by modulating Wnt signaling. Interestingly, studies performed on smooth muscle-specific LRP1-deficient (smLRP1-/-) mice identified a novel and critical role for LRP1 in modulating vascular smooth muscle cell (VSMC) contraction by regulating calcium signaling events. These results uncovered a potential mechanism by which LRP1 protects against aneurysm development. Studies performed on VSMCs isolated from an aneurysm patient, who also contains two heterozygous missense mutations within the LRP1 gene, showed dysregulation of the TGF-β and p53 signaling pathways. These results provide further biological evidence supporting the association of LRP1 with aortic aneurysms. The role of LRP1 in vascular remodeling was also investigated by inducing remodeling in smLRP1-/- mice using the carotid artery ligation model. Our results suggest that LRP1 protects against excessive vascular remodeling by modulating angiotensin II-mediated signaling. Taken together, this work reveals the complex roles of LRP1 in various tissues and provides evidence supporting LRP1 as a critical molecule that integrates metabolic processes with inflammation and vascular disease.
    Description
    2018
    Molecular Medicine
    University of Maryland, Baltimore
    Ph.D.
    Keyword
    Physiology
    Molecular biology
    Biochemistry
    cytoskeletal dynamics
    hepatic inflammation
    LRP1
    Aortic Aneurysm, Abdominal
    Calcium Signaling
    LDL-Receptor Related Proteins
    Vascular Remodeling
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/9002
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    Theses and Dissertations School of Medicine
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