Monday, April 29, 2024
4/29/2024
PROJECT SUMMARY Aneurysms, which are defined as a 50% increase in the diameter of a blood vessel, are an important cause of death worldwide. Aortic aneurysms (AAs) are the most common type and they are divided into two groups: thoracic (TAAs) and abdominal (AAAs). All aneurysms share similar histopathologic features of elastic fiber fragmentation, disorganization and loss of smooth muscle cells (SMCs) and accumulation of collagen and proteoglycans, however, TAAs and AAAs differ in their pathogenesis. While TAAs have a strong genetic predilection, AAAs are considered of atherothrombotic origin. Regardless of type, there is currently no directed medical therapy for AAs, which progressively enlarge over time, increasing the risk of vessel rupture and fatal hemorrhage. Therefore, there is an urgent need to understand the pathogenesis of AAs to devise targeted therapeutic strategies. A single gene mutation is identified in nearly 20% of individuals with TAAs and the genes identified to date largely belong to three functional groups: 1) extracellular matrix (ECM) organization, 2) transforming growth factor b signaling and 3) SMC contractility, which underscores the importance of the interplay between the cell, signaling and the ECM in the pathogenesis of AAs. SMCs have been the focus of investigation in AA pathogenesis, however it is increasingly recognized that endothelial cells (ECs) play a role through endothelial dysfunction. We and others identified mutations in lysyl oxidase (LOX), a gene that encodes an enzyme important for collagen and elastin crosslinking, as a cause of inherited TAAs in humans. Mice homozygous for a Lox mutation identified in humans die perinatally of aneurysm rupture similar to mice lacking LOX, therefore it is challenging to study AA pathogenesis and progression using these models. Our collaborator, Dr. Philip Trackman at the Forsyth Institute, generated a conditional Lox mouse model, which when bred to mice carrying Cre recombinase in certain cell types will lead to deletion or loss of LOX from that cell type. Dr. Trackman generously shared this mouse model with us and we have bred to mice expressing Cre recombinase in ECs, SMCs as well as specific SMCs of the ascending aorta, which are derived from two developmental origins. Our preliminary data show increased proliferation markers in the ascending aorta where aneurysms are present. This observation led us to hypothesize that loss of LOX leads to a phenotypic change in the cell from a differentiated phenotype to a proliferative phenotype contributing to aneurysmal disease. This hypothesis will be explored in this application. Results generated from the proposed studies will not only further our understanding of the role LOX plays in arterial development and maintenance, but they will also help identify new pathways that may be leveraged to develop targeted therapeutic strategies for aneurysmal disease.
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