Grant: Project Grant

A recurrent theme associated with aging processes is an increase cellular oxidative stress. In addition, a chronic low-grade systemic inflammation occurring in the absence of infection has been defined as "inflammaging" and represents a significant risk factor for mortality in the elderly. There are specific inherited mutations that appear to accelerate aging in humans and Werner syndrome (WS) is an interesting example of premature aging. To understand how oxidative stress causes liver diseases that affects 20% of Canadians with age, we generated a mouse model with a mutation of the mouse Werner gene that recapitulates WS including liver diseases. These mice produce a mutant protein that ends up in the wrong place in cells causing a distress in a cellular component called Endoplasmic Reticulum (ER) in the liver tissue. Interestingly, treatments of such mice with vitamin C at weaning reverse all WS anomalies. The liver is an organ that plays a pivotal role in nutrient, drug, hormone, and metabolic waste product processing, thereby maintaining the normal function of other organs in the body. We found that the ER distress is caused by an abnormal increase in oxidative stress in this compartment. We thus hypothesize that a continuous oxidative ER stress causes a low but chronic inflammation in the liver of Werner mice. However, we do not know how exactly a mutation in the Wrn gene causes this oxidative stress in the ER. To answer this question, we propose the following 2 aims: 1) we will determine whether the mislocalized Wrn mutant protein affects the GRP78 interactome in the ER which is an important protein of the ER stress response and 2) we will determine how the Wrn mutant protein induces ER stress and an inflammatory signal. The results generated with our mice will allow us to identify molecular problems (and thus potential therapeutic targets) causing oxidative stress in the ER and inflammation during aging.