Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease. Children with HGPS exclusively die of heart attacks or strokes at an average age of 13 years. The majority of HGPS cases are caused by a mutation C1824T in the lamin A gene. This mutation activates a cryptic splicing site and produces a truncated lamin A mutant named progerin. It is unknown how progerin causes the life-threatening cardiovascular diseases in HGPS patients. Previous research revealed a profound phenotype of massive loss of smooth muscle cells (SMCs) in large arteries in both human patients and HGPS mouse models, strongly suggesting a connection of this phenotype with the cardiovascular malfunction and death associated with HGPS. The primary goal of this proposal is to elucidate the molecular pathway behind this phenotype. Based on a recent study from my group (Zhang et al., PNAS 2014), we hypothesize a mechanism that the presence of progerin destabilizes Poly [ADP-ribose] polymerase 1 (PARP1) protein and leads to the activation of non-homologous end joining (NHEJ), the error-prone DNA repair pathway. Consequently, the mis-repaired chromosomes encounter problems in mitosis, which results in mitotic catastrophe of HGPS SMCs. In this proposal, we propose to test this idea by (i) elucidating how progerin lead to PARP1 down- regulation, (ii) studying the consequence of PARP1 disruption in HGPS SMCs, and (iiI) determining whether attenuation of NHEJ can alleviate SMC loss in HGPS. We will use HGPS patient specific induced pluripotent stem cells (iPSCs) to model SMC loss in vitro as well as apply mouse models of HGPS to test our hypothesis in vivo.
It has been increasingly recognized that the study of rare diseases like progeria can teach us much beyond the disease itself. The proposed study promises to uncover molecular players in smooth muscle cell loss phenotype in progeria and develop new treatments for cardiovascular diseases in HGPS patients as well as for atherosclerosis of aging.
|Atchison, Leigh; Zhang, Haoyue; Cao, Kan et al. (2017) A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells. Sci Rep 7:8168|
|Zhang, Haoyue; Sun, Linlin; Wang, Kun et al. (2016) Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome. PLoS One 11:e0167454|