FIRST LOOK: A Novel Epigenetic Complex Implicated in Thoracic Aortic Aneurysm (TAA)

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The Lindsay laboratory focuses on the clinical expression and molecular etiology of human thoracic aortic aneurysm (TAA). Aneurysm represents the anatomic expression of aortic organ failure with dilation and eventual tear; an event termed “dissection” associated with high mortality. In our research we use human and murine genetics as well as animal modeling to investigate the etiology and pathologic progression of inherited and sporadic aortic disease.

In our work we take advantage of genetic changes (mutations) that cause aortic disease in humans to create cellular models of aortic dysfunction. Through the examination of these cellular models we have discovered novel cell signaling pathways that are specifically activated in the pathologic state. We are primarily interested in how transcriptional regulatory events cause vascular smooth muscle cells (VSMC) to modify phenotype with resultant failure of extracellular matrix homeostasis. Genetic discovery in TAA has identified families of alteration, however mechanistic interconnections amongst groups have remained obscure. A common pathologic feature of TAA tissue involves VSMC phenotypic change with contractile protein deficiency. Using comparative gene expression in human VSMCs we identified activation of a chromatin remodeling complex that mediates deleterious phenotypes of VSMCs across TAA gene families including cytoskeletal disruption and down regulation of contractile protein elements. Genetic or pharmacologic inhibition of the complex slows aortic growth and improves aortic performance in experimental models of TAA.

For more information about Dr. Lindsay’s research, please contact Partners HealthCare Innovation by clicking here.

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