Low density lipoprotein receptor-related protein 1 (LRP1) is a major endocytic and scavenger receptor with the capability to bind over 100+ structurally unrelated ligands and internalize these into cells. This process of receptor mediated endocytosis (RME) allows for ligands to be regulated & cleared from the extracellular space and can be involved with signaling pathway cascades. LRP1 has been implicated in various human diseases across a range of organs and systems. Firstly, LRP1 has an important role in vascular maintenance and homeostasis. Interestingly, studies performed on smooth muscle-specific LRP1-deficient (smLRP1-/-) mice identified novel dysregulated pathways and a critical role for LRP1 in modulating vascular smooth muscle cell (VSMC) contraction by regulating calcium signaling events. These studies have uncovered a protective role for LRP1 against aneurysm formation and development. Collaborators at Johns Hopkins University (Dietz Lab) and the University of Texas Health Science Center (Milewicz Lab) have identified multiple rare human LRP1 variants associated with aortic disease. We hypothesize that genetic variants of LRP1 associated with aneurysm formation will impact endocytic ligand function, transcriptional factor changes and Ca2+ signaling events. We employed radiolabeled ligands to ascertain differences in endocytic function of rare LRP1 variants in vitro and found there is dysregulated internalization of activated alpha-2-macroglobulin (a2M*) in primary patient VSMCs harboring mutations associated with abdominal aortic aneurysm (AAA) formation. Furthermore, we saw no conclusive differences in internalization of a2M* in cells transfected with LRP1 plasmids containing isolated rare variants of interest. From analysis of primary patient cells harboring variants, we observed elevated levels of Myocardin-related transcription factor A (MRTFA). Upon analysis of both Wild type (WT), Knockout (KO) and Patient Derived (Pt) induced pluripotent stem cells (iPSCs), we did not see any quantifiable differences in the distribution of MRFTA in either the cytoplasm or nucleus of cells. Lastly, we interrogated the involvement of Ca2+ signaling in these cells and saw noticeable differences in the levels of α2δ-1, a critical subunit of Cav1.2, along with altered Ca2+ flux in these cells. Another aim of this project is to investigate the role of LRP1 in SARS-CoV-2 viral entry. The global COVID19 pandemic that is still having severe effects on both individual lives and economies around the world. Despite significant advances in our understanding of SARS-CoV-2 infectivity, questions remain about additional host factors that facilitate cell entry of viral particles, and to date several host factors/auxiliary receptors have been identified that facilitate SARS-CoV-2 endocytosis. Recent studies have provided evidence suggesting that LRP1 may also function as an auxiliary host factor for SARS-CoV-2. Therefore, we sought to test the hypothesis that LRP1 may function as a co-receptor with ACE2 to facilitate viral entry of SARS-CoV-2. using surface plasmon resonance technology, cellular mediated endocytosis experiments and pseudovirion (PV) particles. Receptors of interest were immobilized on CM5 chips (LRP1, VLDLR, LRP1 clusters and LRP2). Various proteins including trimeric spike, Spike S1 subunit and the receptor binding domain (RBD) of Spike were flowed over their respective flow cells on chips. We confirmed high affinity binding of purified trimeric spike protein to LRP1, as well as S1 subunit of the spike protein with a KD value of 72 ± 14 nM and a KD value of 38 ± 18 nM, respectively. We performed competition experiments and found that the presence of RAP, an LRP1 antagonist, as well as EDTA, which removes structural calcium from LRP1 ligand binding repeats, ablate this binding. Cellular internalization assays were performed in cells using 125I-labeled SARS-CoV-2 S1 subunit and saw increased internalization of Spike protein in the presence of LRP1. Western blot analysis was performed to confirm overexpression of proteins of interest in various cell types for internalization assays. Lastly, pseudovirions particles expressing Spike protein were generated and utilized for studies. LRP1 and ACE2 were overexpressed in HEK293T/17 cells and luciferase activity was quantified after infectivity. In summary, our results demonstrate that LRP1 has a critical role in two different human health issues. First, rare variants of LRP1 associated with aneurysm formation have functional deficits in LRP1 and this furthermore implicates LRP1 as an important regulator of the vasculature and extracellular matrix (ECM). Secondly, we establish a strong link between LRP1 and components of SARS-CoV-2 as well as the major receptor binding partner for SARS-CoV-2: ACE2. These results identify the potential of LRP1 to enhance ACE2-mediated SARS-CoV-2 viral entry.