The role of mutant Lamin A in myeloid cells in Hutchinson-Gilford progeria syndrome

About This Grant

Project Summary: Hutchinson-Gilford progeria syndrome (HGPS) is a rapid, progressive aging disease caused be a de novo point mutation in the LMNA gene. The mutation causes missplicing of LMNA and production of a mutant mRNA and truncated protein called progerin. Progerin accumulation exerts a dominant negative effect on wild type LMNA, leading to DNA damage, proinflammatory gene activation, premature senescence and ultimately cell death. Children with HGPS die of accelerated atherosclerotic vascular disease. A notable pathologic feature of HGPS vascular disease is progressive loss of vascular smooth muscle cells with a simultaneous increase in inflammatory cells in the tunica adventitia and extensive periadventitial fibrosis. Some of these features are shared with other aging-associated cardiovascular diseases including hypertension and arteriosclerosis. Thus, a better understanding of how adventitial inflammation amplified vascular disease in HGPS may have implications for more common forms of aging in the cardiovascular system. In preliminary data we have found that HGPG aortas from a mouse model of disease harbor accumulation of Mac2 positive macrophage cells in the adventitia. On single-cell RNA sequencing we observe a significant increase in proinflammatory macrophage gene expression with enrichment for pathways involving interferon and tumor necrosis alpha pathways. Our central hypothesis is that progerin expression in bone-marrow derived myeloid cells promote vascular inflammation in HGPS. To test this hypothesis we will pursue the following two Specific Aims: 1) determine the contribution of myeloid-expressed mutant Lamin A (i.e. progerin) in adventitial fibrosis and vascular disease; 2) develop in vitro human stem cell models of HGPS to dissect the impact of Lamin dysfunction in myeloid cell differentiation and function. This project will explore a novel mechanism in HGPS- associate vascular disease, which has broader implications for how adventitial inflammation derived from bone- marrow cells may promote more common forms of atherosclerosis in humans.