My Research

 Hutchinson Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease caused by a mutant protein called “progerin” that is responsible for the overall cellular toxicity and organismal decline. HGPS patients die due to cardiovascular problems at an average age of 14 years. Autopsies show abnormal blood vessels (arteries). Arteries are mainly formed by vascular smooth muscle cells (VSMCs), which are critical for vessel contraction and blood flow. HGPS patients have vessels with very few VSMCs, leading to vascular stiffness. Understanding the loss of VSMCs might be crucial to find a cure.

 

 In our group we have found that progerin has a strong effect hindering DNA replication, causing DNA damage/genomic instability. Currently I am aiming to elucidate the crosstalk between DNA damage and repair with progerin-induced vascular disease.

 

Given that progerin also accumulates in the vessels of patients in normal aging individuals, my findings could have a more general application to cardiovascular disease other than HGPS, my results may provide keys for treating millions of adults with cardiovascular problems associated with the natural aging process.

 

With Alexandra, one girl among 20 million.

Selected Publications

Calcitriol Prevents RAD51 Loss and cGAS-STING-IFN Response Triggered by Progerin

Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced “progerin” has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin‐induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease‐mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1‐regulated interferon (IFN)‐like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin‐expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated‐RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin‐expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.

A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by a truncated lamin A protein (progerin) that drives cellular and organismal decline. HGPS patient-derived fibroblasts accumulate genomic instability, but its underlying mechanisms and contribution to disease remain poorly understood. Here, we show that progerin-induced replication stress (RS) drives genomic instability by eliciting replication fork (RF) stalling and nuclease-mediated degradation. Rampant RS is accompanied by upregulation of the cGAS/STING cytosolic DNA sensing pathway and activation of a robust STAT1-regulated interferon (IFN)-like response. Reducing RS and the IFN-like response, especially with calcitriol, improves the fitness of progeria cells and increases the efficiency of cellular reprogramming. Importantly, other compounds that improve HGPS phenotypes reduce RS and the IFN-like response. Our study reveals mechanisms underlying progerin toxicity, including RS-induced genomic instability and activation of IFN-like responses, and their relevance for cellular decline in HGPS.

My publications at PubMed®